Pyrazolopyrimidine compounds

ABSTRACT

The present teachings provide a compound represented by structural formula (I-0), or a pharmaceutically acceptable salt thereof. Also described are pharmaceutical compositions and methods of use thereof.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/443,072, filed May 15, 2015 and now U.S. Pat. No. 9,573,954,which is a U.S. national stage filing under 35 U.S.C. § 371(c), ofInternational Application No. PCT/CA2013/000957, filed Nov. 15, 2013,which, in turn, claims the benefit of U.S. Provisional Application No.61/727,581, filed Nov. 16, 2012, and U.S. Provisional Application No.61/808,152, filed Apr. 3, 2013. The entire teachings of each of theaforementioned applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Protein kinases have been the subject of extensive study in the searchfor new therapeutic agents in various diseases, for example, cancer.Protein kinases are known to mediate intracellular signal transductionby effecting a phosphoryl transfer from a nucleoside triphosphate to aprotein acceptor that is involved in a signaling pathway. There are anumber of kinases and pathways through which extracellular and otherstimuli cause a variety of cellular responses to occur inside the cell.

Human TTK protein kinase (TTK), also known as tyrosine threonine kinase,dual specificity protein kinase TTK, Monopolar Spindle 1 (Mps1) andPhosphotyrosine-Picked Threonine Kinase (PYT), is a conservedmultispecific kinase that is capable of phosphorylating serine,threonine and tyrosine residues when expressed in E. coli (Mills et al.,J. Biol. Chem. 22(5): 16000-16006 (1992)). TTK mRNA is not expressed inthe majority of physiologically normal tissues in human (Id). TTK mRNAis expressed in some rapidly proliferating tissues, such as testis andthymus, as well as in some tumors (for example, TTK mRNA was notexpressed in renal cell carcinoma, was expressed in 50% of breast cancersamples, was expressed in testicular tumors and ovarian cancer samples)(Id). TTK is expressed in some cancer cell lines and tumors relative tonormal counterparts (Id.; see also WO 02/068444 A1).

Therefore, agents which inhibit a protein kinase, in particular TTK,have the potential to treat cancer. There is a need for additionalagents which can act as protein kinase inhibitors, in particular TTKinhibitors.

In addition, cancer recurrence, drug resistance or metastasis is one ofthe major challenges in cancer therapies. Cancer patients who respondedfavorably to the initial anti-cancer therapy often develop drugresistance and secondary tumors that lead to the relapse of the disease.Recent research evidences suggest that the capability of a tumor to growand propagate is dependent on a small subset of cells within the tumor.These cells are termed tumor-initiating cells (TICs) or cancer stemcells. It is thought that the TICs are responsible for drug resistance,cancer relapse and metastasis. Compounds that can inhibit the growth andsurvival of these tumor-initiating cells can be used to treat cancer,metastasis or prevent recurrence of cancer. Therefore, a need exists fornew compounds that can inhibit the growth and survival oftumor-imitating cells.

SUMMARY OF THE INVENTION

Applicants have now discovered that certain pyrazolotriazine andpyrazolopyrimidine compounds are potent kinase inhibitors, such as TTKprotein kinase (see Example B). Applicants have also discovered thatthese compounds have potent anticancer activity against pancreaticcancer, prostate cancer, lung cancer, melanoma, breast cancer, coloncancer, and ovarian cancer cells in cell culture study (see ExamplesC-D). Based on these discoveries, pyrazolotriazine andpyrazolopyrimidine compounds, pharmaceutical compositions thereof, andmethods of treating cancer with the pyrazolotriazine andpyrazolopyrimidine compounds are disclosed herein.

The present teachings are directed, at least in part, to a compoundrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CH;

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which aresubstituted with —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵, —C(═S)NR^(d)R^(e), or—NHC(═S)R⁵ and optionally substituted with one or more groups selectedfrom one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1), —OR^(c1), —SR^(c1), —SOR^(c1), or —SO₂R^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenylor optionally substituted 5-10 membered heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(a1) and R^(b1), together with the nitrogen to which they areattached, form an optionally substituted 3-7 membered ring;

R^(a2) and R^(b2) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they areattached, form an optionally substituted 3-8 membered ring (e.g., abridged bicyclic ring);

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(d) and R^(e) are each independently selected from —H, optionallysubstituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached,form an optionally substituted 3-7 membered ring.

In one embodiment, the present teachings include a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a compound represented by structural formula (I-0) described aboveor a pharmaceutically acceptable salt thereof.

In another embodiment, the present teachings provide a method oftreating a subject having cancer comprising administering to the subjectan effective amount of a compound of structural formula (I-0) or apharmaceutically acceptable salt thereof.

Another embodiment of the present teachings provides a method ofinhibiting TTK activity in a subject in need of inhibition of TTKactivity, comprising administering to the subject an effective amount ofa compound represented by Structural Formula (I-0) or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the present teachings includes the use of acompound represented by Structural Formula (I-0) or a pharmaceuticallyacceptable salt thereof in therapy. In some embodiments, the therapy isfor treating a subject with cancer. Alternatively, the therapy is forinhibiting TTK activity in a subject in need of inhibition of TTKactivity.

Another embodiment of the present teachings includes the use of acompound represented by Structural Formula (I-0) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for treatinga subject with cancer.

Another embodiment of the present teachings includes the use of acompound represented by Structural Formulas (I-0) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament forinhibiting TTK activity in a subject in need of inhibition of TTKactivity.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present teachings are directed to a compoundrepresented by Structural Formula (I-0) or a pharmaceutically acceptablesalt thereof; and values and alternative values for the variables inStructural Formula (I-0) are provided in the following paragraphs:

In a first embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CH;

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which aresubstituted with —C(═O)NR^(d)R^(e) or —NHC(═O)R⁵, and optionallysubstituted with one or more groups selected from halogen, hydroxy,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1) or —OR^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenylor optionally substituted 5-6 membered monocyclic heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl;

R^(a2) and R^(b2) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they areattached, form an optionally substituted 3-7 membered ring;

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl; and

R^(d) and R^(e) are each independently selected from —H, optionallysubstituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached,form an optionally substituted 3-7 membered ring.

In a second embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein:

R is phenyl or monocyclic 5-6 membered heteroaryl, both of which aresubstituted with —C(═O)NR^(d)R^(e), —NHC(═O)R⁵, —C(═S)NR^(d)R^(e), or—NHC(═S)R⁵ and optionally substituted with one or more groups selectedfrom halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy,and (C₁-C₃)haloalkoxy;

R¹ is —NR^(a1)R^(b1), —OR^(c1), —SR^(c1), —SOR^(c1), or —SO₂R^(c1);

R² is —NR^(a2)R^(b2), —OR^(c2), —SR^(c2), optionally substituted phenylor optionally substituted 5-6 membered monocyclic heteroaryl;

R⁵ is optionally substituted (C₁-C₃)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(a1) and R^(b1) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl;

R^(a2) and R^(b2) are each independently selected from —H, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(a2) and R^(b2), together with the nitrogen to which they areattached, form an optionally substituted 3-7 membered ring;

R^(c1) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇) cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl;

R^(c2) is optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5-6 membered monocyclic heteroaryl; and

R^(d) and R^(e) are each independently selected from —H, optionallysubstituted (C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5-6 memberedmonocyclic heteroaryl; or

R^(d) and R^(e), together with the nitrogen to which they are attached,form an optionally substituted 3-7 membered ring.

In a third embodiment, the compound is represented by structuralformula:

or a pharmaceutically acceptable salt thereof, wherein R³ is—C(═O)NR^(d)R^(e) or NHC(═O)R⁵; each R⁴ is independently selected fromhydrogen, halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; and m is 1, 2, or 3; and values for the remainder of thevariables are as described for Structural Formula (I) or in the secondembodiment.

In a fourth embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof; and values for theremainder of the variables are as described for Structural Formula(I-0), (I), or (I)′, or in the first, second, or third embodiment.

In a fifth embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein X is NH or O; R⁵is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which isoptionally substituted with one or more groups selected from halogen,hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R¹¹ is(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each ofwhich is optionally substituted with one or more groups selected fromhalogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, —C(═O)NH₂, —C(═O)NH(C₁-C₃)alkyl, —C(═O)N((C₁-C₃)alkyl)₂,and —SO₂(C₁-C₃)alkyl; R^(d) is independently selected from —H,(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 4-5 membered heterocycloalkyl whereineach of the (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, and 4-5 memberedheterocycloalkyl is optionally substituted with one or more groupsselected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; n is 0, 1, 2, or 3; and values and alternative values forthe remainder of the variables are as described for Structural Formula(I) or in the second or third embodiment.

In a sixth embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I) or in the second, third, or fifth embodiment.

In a seventh embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I), or in the second, third, or fifthembodiment.

In an eighth embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2),R^(b2) is —H or CH₃; and values and alternative values for the remainderof the variables are as described for Structural Formula (I), or in thesecond, third, or fifth embodiment.

In a ninth embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2),R^(a2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl(preferably, 3-7 membered monocyclic heterocycloalkyl, phenyl, and 5-6membered monocyclic heteroaryl); wherein each of which is optionallysubstituted with one or more groups selected from halogen, hydroxy, CN,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃)hydroxyalkyl, 3-7membered monocyclic heterocycloalkyl; and values and alternative valuesfor the remainder of the variables are as described for StructuralFormula (I), or in the second, third, fifth, or eighth embodiment.

In a tenth embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2),R^(a2) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl,tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, orphenyl (preferably, methyl, propyl, butyl, pentyl, cyclopentyl,cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl; morepreferably, oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl,piperidinyl, pyridyl, or phenyl), wherein each of the methyl, ethyl,propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, oxetanyl, tetrahydro-2H-pyranyl,tetrahydrofuranyl, piperidinyl, pyridyl, and phenyl (preferably, methyl,propyl, butyl, pentyl, cyclopentyl, cyclohexyl, oxetanyl,tetrahydro-2H-pyranyl, tetrahydrofuranyl; more preferably, oxetanyl,tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl, pyridyl, orphenyl) is optionally substituted with one or more groups selected fromhalogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, andoxetanyl; and values and alternative values for the remainder of thevariables are as described for Structural Formula (I), or in the second,third, fifth, eighth or ninth embodiment.

In an eleventh embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), or (II-A2),R^(a2) and R^(b2), together with the nitrogen to which they areattached, form a 3-7 membered monocyclic heterocycloalkyl, optionallysubstituted with one or more groups selected from halogen, CN, hydroxy,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy,—C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and 3-7 memberedmonocyclic heterocycloalkyl; and values and alternative values for theremainder of the variables are as described for Structural Formula (I),or in the second, third, or fifth embodiment.

Alternatively, R^(a2) and R^(b2), together with the nitrogen to whichthey are attached, form piperidinyl, morpholinyl, or piperazinyl(preferably, morpholinyl), wherein each substitutable carbon atom in thepiperidinyl, morpholinyl, or piperazinyl (preferably, morpholinyl) isoptionally substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxyalkyl or (C₁-C₃)alkoxy; and eachsubstitutable nitrogen atom in the piperazinyl is optionally substitutedwith (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl,(C₃-C₅)cycloalkyl, —C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl,oxetanyl, or —C(═O)H.

In a twelfth embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I), or in the second, third, fifth, or sixthembodiment.

In a thirteen embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-D1), or (II-A2),R^(c2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl(preferably, 3-7 membered monocyclic heterocycloalkyl, phenyl, or 5-6membered monocyclic heteroaryl), each of which is optionally substitutedwith one or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy,—C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)H, and 3-7 memberedmonocyclic heterocycloalkyl; and values and alternative values for theremainder of the variables are as described for Structural Formula (I),or in the second, third, or fifth embodiment.

In a fourteenth embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-D1), or (II-A2),R^(c2) is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl,phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,or azetidinyl (preferably, cyclopentyl, cyclohexyl, oxetanyl,tetrahydrofuranyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, azetidinyl,pyrrolidinyl, piperidinyl; more preferably, tetrahydro-2H-pyranyl,phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,or azetidinyl), wherein each substitutable carbon atom in thecyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl,pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl andazetidinyl (preferably, cyclopentyl, cyclohexyl, oxetanyl,tetrahydrofuranyl, tetrahydro-2H-pyranyl, phenyl, pyridyl, azetidinyl,pyrrolidinyl, and piperidinyl; more preferably, tetrahydro-2H-pyranyl,phenyl, pyridyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,and azetidinyl) is optionally substituted with one or more groupsselected from halogen, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, oxetanyl; and each substitutablenitrogen atom in the azetidinyl, pyrrolidinyl, or piperidinyl, isoptionally substituted with (C₁-C₃)alkyl, (C₃-C₅)heterocycloalkyl,(C₁-C₃)hydroxylalkyl, C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₅)cycloalkyl, or—C(═O)H; and values and alternative values for the remainder of thevariables are as described for Structural Formula (I), or in the second,third, fifth, or thirteenth embodiment.

In a fifteenth embodiment, for compounds represented by any one ofstructural formulae (I-A), (II-A1), (II-B1), (II-C1), (II-D1), or(II-A2), R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl(preferably, R⁴ is chlorine or methyl; and is ortho to—C(═O)NR^(d)R^(e)); and values and alternative values for the remainderof the variables are as described for Structural Formula (I), or in thethird, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth,thirteenth, or fourteenth embodiment.

In a sixteenth embodiment, for compounds represented by any one ofstructural formulae (I), (I-A), (II-A1), (II-B1), (II-C1), (II-D1), or(II-A2), R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl (preferably, R^(d)is cyclopropyl), wherein both of which are optionally substituted withone or more groups selected from halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and values and alternative valuesfor the remainder of the variables are as described for StructuralFormula (I), or in the third, fifth, sixth, seventh, eighth, ninth,tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenthembodiment.

In a seventeenth embodiment, for compounds represented by any one ofstructural formulae (II-A1), (II-B1), (II-C1), (II-D1), or (II-A2), R¹¹is (C₁-C₆)alkoxy, ethyl, propyl, isopropyl, isobutyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl,tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl,or oxetanyl (preferably, methoxy, ethyl, isopropyl, cyclohexyl,morpholinyl, tetrahydro-2H-pyranyl, pyridinyl, or oxetanyl), whereineach substitutable carbon atom in the ethyl, propyl, isopropyl,isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl,imidazolyl, and oxetanyl (preferably, methoxy, ethyl, isopropyl,cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl, pyridinyl, or oxetanyl)is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen atomin the piperazinyl is optionally substituted with (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, oxetanyl, tetrahydro-2H-pyranyl,—C(═O)(C₃-C₅)cycloalkyl, —C(═O)(C₁-C₃)alkyl, or —C(═O)H; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I), or in the fifth, sixth, seventh, eighth,ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, orsixteenth embodiment.

In a eighteenth embodiment, for compounds represented by any one ofstructural formulae (I-0), (I), (I)′, (I-A), or (II-A0), R¹ is—NHR^(b1), R^(b1) is (C₁-C₄)alkyl optionally substituted with one ormore groups selected from hydroxy, (C₁-C₃)alkoxy, hydroxy(C₁-C₃)alkyl,—SO₂(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, or 3-7 membered heterocycloalkylcontaining one ring heteroatom, the heteroatom being oxygen, wherein the(C₃-C₇)cycloalkyl or the 3-7 membered heterocycloalkyl substituent isoptionally substituted with halogen, hydroxyl, or (C₁-C₃)alkyl;alternatively, R^(b1) is (C₁-C₄)alkyl optionally substituted with one ormore groups selected from hydroxy, (C₁-C₃)alkoxy, hydroxymethyl,—SO₂(C₁-C₃)alkyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, wherein the cyclobutyl,cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranylsubstituent is optionally substituted with 1-2 groups selected fromhydroxy or (C₁-C₃)alkyl; and values and alternative values for theremainder of the variables are as described for Structural Formula(I-0), (I), or (I)′, or in the first, second, third, or fourthembodiment.

Preferably in the eighteenth embodiment, R¹ is represented by the one ofthe following structural formulae:

In a nineteenth embodiment, for compounds represented by any one ofstructural formulae (I-0), (I), (I)′, (I-A), or (II-A0), R¹ is—NHR^(b1), R^(b1) is (C₁-C₄)alkyl optionally substituted with one ormore groups selected from i) 4-6 membered heterocycloalkyl substitutedwith —N(R^(a1))₂, wherein the heterocycloalkyl contains one ringheteroatom which is oxygen; ii) —N(R^(a1))₂; iii) 4-6 memberedheterocycloalkyl containing one ring heteroatom which is nitrogen; oriv) 5-6 membered nitrogen-containing heteroaryl; wherein R^(a1) is H or(C₁-C₃)alkyl; and the 4-6 membered heterocycloalkyl or 5-6 memberednitrogen-containing heteroaryl substituent is optionally substitutedwith one or more groups selected from (C₁-C₃)alkyl, hydroxy, halogen,—NH₂, —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂; alternatively, R^(b1) is(C₁-C₄)alkyl optionally substituted with one or more groups selectedfrom tetrahydropyranyl substituted with —N(R^(a1))₂; N(R^(a1))₂;morpholinyl; piperazinyl; piperidinyl; pyridinyl; and imidazolyl;wherein the morpholinyl, piperazinyl, piperidinyl, pyridinyl, orimidazolyl substituent is optionally substituted with 1-2 groupsselected from (C₁-C₃)alkyl, halo, or hydroxyl; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I-0), (I), or (I)′, or in the first, second,third, or fourth embodiment.

Preferably in the nineteenth embodiment, R¹ is represented by the one ofthe following structural formulae:

In a twentieth embodiment, for compounds represented by any one ofstructural formulae (I-0), (I), (I)′, (I-A), (II-A0), (II-A1), (II-A2),or (II-B1), R² is R^(c2) or —OR^(c2), and R^(c2) is (C₃-C₇)cycloalkyl;4-7 membered heterocycloalkyl containing one ring heteroatom which isoxygen; phenyl; or 5-6 membered nitrogen-containing heteroaryl; each ofwhich is optionally substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, or —SO₂(C₁-C₃)alkyl; alternatively, R^(c2) is cyclobutyl,cyclopentyl, cyclohexanyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, phenyl, pyrazolyl, or pyridyl-N-oxide, each of whichis optionally substituted with one or more groups selected from halogen,hydroxy, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, —SO₂(C₁-C₃)alkyl; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I-0), (I), or (I)′, or in the first, second,third, fourth, eighteenth, or nineteenth embodiment.

Preferably in the twentieth embodiment, R² is represented by the one ofthe following structural formulae:

In a twenty first embodiment, for compounds represented by any one ofstructural formulae (I-0), (I), (I)′, (I-A), (II-A0), (II-A1), (II-A2),or (II-B1), R² is

4-10 membered heterocycloalkyl containing one ring heteroatom which isnitrogen optionally substituted with hydroxy, hydroxy(C₁-C₃)alkyl,—C(═O)(C₁-C₃)alkyl, or (C₃-C₇)cycloalkyl;

5-10 membered nitrogen-containing heteroaryl;

OR^(c2), wherein R^(c2) is phenyl optionally substituted with halogen,(C₁-C₃)alkyl, —N(R^(a1))₂ or 4-6 membered heterocycloalkyl containingone ring heteroatom which is nitrogen; pyridinyl optionally substitutedwith halogen or (C₁-C₃)alkyl; piperidinyl optionally substituted with4-6 membered heterocycloalkyl containing one ring heteroatom which isoxygen, or (C₁-C₃)alkoxy; pyrrolidinyl optionally substituted with 4-6membered heterocycloalkyl containing one ring heteroatom which is oxygenor (C₁-C₃)alkoxy; or azetidinyl optionally substituted with 4-6 memberedheterocycloalkyl containing one ring heteroatom which is oxygen or(C₁-C₃)alkoxy; wherein R^(a1) is H or (C₁-C₃)alkyl, or

NHR^(b2) or N((C₁-C₃)alkyl)R^(b2) wherein R^(b2) is (C₁-C₄)alkyl,(C₃-C₇)cycloalkyl, 3-7 membered heterocycloalkyl containing one ringheteroatom which is oxygen, phenyl, or 5-6 membered nitrogen-containingheteroaryl;

-   -   wherein the (C₁-C₄)alkyl represented by R^(b2) is optionally        substituted with one or more groups selected from hydroxy,        —C(═O)NH₂, (C₁-C₄)alkyl, hydroxy(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl,        3-7 membered heterocycloalkyl containing one ring heteroatom        which is oxygen, and wherein the (C₃-C₇)cycloalkyl, 3-7 membered        heterocycloalkyl, phenyl, and 5-6 membered nitrogen-containing        heteroaryl substituents in the group represented by R^(b2) are        optionally substituted with hydroxy, halogen, (C₁-C₃)alkyl,        (C₁-C₃)alkoxy, hydroxy(C₁-C₃)alkyl.

Alternatively in the twenty first embodiment, R² is

azetidinyl optionally substituted with hydroxyl, hydroxymethyl,(C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; pyrrolidinyl optionallysubstituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl, or—C(═O)(C₁-C₃)alkyl; piperidinyl optionally substituted with hydroxyl,hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl; piperazinyloptionally substituted with hydroxyl, hydroxymethyl, (C₃-C₆)cycloalkyl,or —C(═O)(C₁-C₃)alkyl; morpholinyl optionally substituted with hydroxyl,hydroxymethyl, (C₃-C₆)cycloalkyl, or —C(═O)(C₁-C₃)alkyl;

pyridinyl, quinolinyl,

OR^(c2), wherein R^(c2) is phenyl optionally substituted with—N(R^(a1))₂ or with 4-6 membered heterocycloalkyl with one ringheteroatom which is nitrogen; pyridinyl optionally substituted withhalogen; piperidinyl optionally substituted with oxetanyl; orpyrrolidinyl optionally substituted with oxetanyl; wherein R^(a1) is Hor (C₁-C₃)alkyl;

—NH-cyclopentyl, —N—((C₁-C₃)alkyl)-cyclopentyl or NHR^(b2), whereinR^(b2) is phenyl or pyridinyl, each of which is optionally substitutedwith halo or (C₁-C₃)alkyl;

cyclopropyl optionally substituted with hydroxyl, hydroxymethyl, oroxetanyl; cyclobutyl optionally substituted with hydroxyl,hydroxymethyl, or oxetanyl; cyclopentyl optionally substituted withhydroxyl, hydroxymethyl, or oxetanyl; cyclohexanyl optionallysubstituted with hydroxyl, hydroxymethyl, or oxetanyl;

tetrahydropyranyl optionally substituted with hydroxyl or hydroxymethyl,tetrahydrofuranyl optionally substituted with hydroxyl or (C₁-C₃)alkoxy;oxetanyl; or

(C₁-C₄)alkyl, wherein the (C₁-C₄)alkyl is optionally substituted withone or more groups selected from hydroxy, —C(═O)NH₂, (C₁-C₄)alkoxy,hydroxy(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, 3-6 membered heterocycloalkylcontaining one ring heteroatom which is oxygen; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I-0), (I), or (I)′, or in the first, second,third, fourth, eighteenth, or nineteenth embodiment.

Preferably in the twenty first embodiment, R² is represented by the oneof the following structural formulae:

In a twenty second embodiment, for compounds represented by structuralformula (I-0) or (II-A0), R² is R¹ is —NH—(CH₂)_(x)—Cy, wherein x is 1or 2, and Cy is morpholinyl or piperidinyl optionally substituted with(C₁-C₃)alkyl or F; and R² is —O-phenyl optionally substituted with oneor two F. Alternatively, R¹ is —NH—(CH₂)_(x)—Cy, wherein x is 1 or 2,and Cy is —N-morpholinyl, -piperidyl N-substituted with (C₁-C₃)alkyl or—N-piperidyl optionally substituted with fluorine; and R² is —O-phenyloptionally substituted with one or two F. Alternatively, R¹ is—NH—CH₂—Cy, wherein Cy is C₃-C₄ cycloalkyl optionally substituted withone or two groups selected from alkyl and hydroxyl; or 4-6 memberedheterocycloalkyl containing one ring heteroatom atom which is oxygen;and R² is —O-pyridinyl; —NH—(C₂-C₆)hydroxyalkyl optionally substitutedwith cyclopropyl or isopropyl; or —NH—(C₃-C₆)cycloalkyl optionallysubstituted with hydroxyl or (C₁-C₂)hydroxylalkyl. Values andalternative values for the remainder of the variables are as describedfor Structural Formula (I-0).

Alternatively for the 22^(nd) embodiment, the following compounds orpharmaceutically acceptable salts thereof are excluded:

In a twenty third embodiment, the compound is represented by thefollowing structural formula:

or a pharmaceutically acceptable salt thereof, wherein R³ is—C(═O)NR^(d)R^(e) or —NHC(═O)R⁵; each R⁴ is independently selected fromhalogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; andm is 0, 1, 2, or 3; and values and alternative values for the remainderof the variables are as described for Structural Formula (I)′.

In a twenty fourth embodiment, the compound is represented by thefollowing structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is NH or O;

R⁵ is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which isoptionally substituted with one or more groups selected from halogen,hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;

R¹¹ is (C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each ofwhich is optionally substituted with one or more groups selected fromhalogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, —C(═O)NH₂, and —SO₂CH₃;

R^(d) and R^(e) are each independently selected from —H, (C₁-C₇)alkyl,(C₃-C₇) cycloalkyl, wherein each of the (C₁-C₃)alkyl and(C₃-C₇)cycloalkyl is optionally substituted with one or more groupsselected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; and

n is 0, 1, 2, or 3;

and values and alternative values for the remainder of the variables areas described for Structural Formula (I)′ or in the twenty thirdembodiment.

In a twenty fifth embodiment, the compound is represented by thefollowing structural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I)′ or in the twenty third or twenty fourthembodiment.

In a twenty sixth embodiment, the compound is represented by thefollowing structural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I)′ or in the first, twenty third, twentyfourth, or twenty fifth embodiment.

In a twenty seventh embodiment, for compounds represented by any one ofstructural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or(II-A2)′, R^(b2) is —H or CH₃; and values and alternative values for theremainder of the variables are as described for Structural Formula (I)′,or in the first, twenty third, twenty fourth, twenty fifth, or twentysixth embodiment.

In a twenty eighth embodiment, for compounds represented by any one ofstructural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or(II-A2)′, R² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl;wherein each of which is optionally substituted with one or more groupsselected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; alternatively, R^(a2) is methyl, ethyl, t-butyl,cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl, or phenyl,wherein each of the cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl,pyridyl, and phenyl is optionally substituted with one or more groupsselected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; and values and alternative values for the remainder ofthe variables are as described for Structural Formula (I)′, or in thefirst, twenty third, twenty fourth, twenty fifth, twenty sixth, ortwenty seventh embodiment.

In a twenty ninth embodiment, for compounds represented by any one ofstructural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, or(II-A2)′, R^(a2) and R^(b2), together with the nitrogen to which theyare attached, form a 3-7 membered monocyclic heterocycloalkyl,optionally substituted with one or more groups selected from halogen,CN, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl,(C₁-C₃)alkoxy, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and3-7 membered monocyclic heterocycloalkyl; alternatively, R^(a2) andR^(b2), together with the nitrogen to which they are attached, formpiperidinyl, morpholinyl, or piperazinyl, wherein each substitutablecarbon atom in the piperidinyl, morpholinyl, or piperazinyl isoptionally substituted with halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen atomin the piperazinyl is optionally substituted (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl,—C(═O)(C₁-C₃)alkyl, oxetanyl, or —C(═O)H; and values and alternativevalues for the remainder of the variables are as described forStructural Formula (I)′, or in the first, twenty third, twenty fourth,twenty fifth, twenty sixth, or twenty seventh embodiment.

In a thirtieth embodiment, the compound is represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof; and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I)′, or in the first, twenty third, twentyfourth, or twenty fifth embodiment.

In a thirty first embodiment, for compounds represented by any one ofstructural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, (II-D1)′, or(II-A2)′, R^(c2) is (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each ofwhich is optionally substituted with one or more groups selected fromhalogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl,(C₁-C₃)alkoxy, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, and —C(═O)H;alternatively, R^(c2) is cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl,phenyl, pyridyl, or azetidinyl, wherein each of the cyclopentyl,cyclohexyl, tetrahydro-2H-pyranyl, phenyl, and pyridyl is optionallysubstituted with one or more groups selected from halogen, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, and (C₁-C₃)alkoxy; and thenitrogen in the azetidinyl is optionally substituted with (C₁-C₃)alkyl,(C₁-C₃)hydroxylalkyl, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₅)cycloalkyl, or—C(═O)H; and values and alternative values for the remainder of thevariables are as described for Structural Formula (I)′, or in the first,twenty third, twenty fourth, or twenty fifth embodiment.

In a thirty second embodiment, for compounds represented by any one ofstructural formulae (II-A1)-(II-D1), (II-A1)′-(II-D1)′, (II-A2), or(II-A2)′, X is NH; and values and alternative values for the remainderof the variables are as described for Structural Formula (I) or (I)′, orin the fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth,thirteenth, fourteenth, twenty fourth, twenty fifth, twenty sixth,twenty seventh, twenty eighth, twenty ninth, thirtieth, or thirty firstembodiment. Alternatively, X is O.

In a thirty third embodiment, for compounds represented by any one ofstructural formulae (I-A)′, (II-A1)′, (II-B1)′, (II-C1)′, (II-D1)′, or(II-A2)′, R⁴ is selected from hydrogen, halogen, and (C₁-C₃)alkyl(preferably, R⁴ is chlorine or methyl; and is ortho to—C(═O)NR^(d)R^(e)); and values and alternative values for the remainderof the variables are as described for Structural Formula (I)′, or in thetwenty third, twenty fourth, twenty fifth, twenty sixth, twenty seventh,twenty eighth, twenty ninth, thirtieth, thirty first, thirty secondembodiment.

In a thirty fourth embodiment, for compounds represented by any one ofstructural formulae (II-A1)′, (II-B1)′, or (II-A2)′, R¹¹—(CH₂)_(n)—X— isrepresented by the one of the following structural formulae:

and values and alternative values for the remainder of the variables areas described for Structural Formula (I)′, or in the first, twenty third,twenty fourth, or twenty fifth embodiment.

In a thirty fifth embodiment, for compounds represented by any one ofstructural formulae (I)′, (I-A)′, (II-A1)′, (II-B1)′, or (II-A2)′, R² isrepresented by the one of the following structural formulae:

and values and alternative values for the remainder of the variables areas described for Structural Formula (I)′, or in the first, twenty third,twenty fourth, or twenty fifth embodiment.

In a thirty sixth embodiment, for compounds represented by any one ofstructural formulae (I-0), (I), (I)′, (I-A), (I-A)′, (II-A0), (II-A1)′,(II-B1)′, or (II-A2)′, R⁴ is selected from hydrogen, halogen, and(C₁-C₃)alkyl (preferably, R⁴ is chlorine or methyl; and is ortho to—C(═O)NR^(d)R^(e)); and values and alternative values for the remainderof the variables are as described for Structural Formula (I-0), (I),(I)′, (I-A), (II-A0), or in the eighteenth, nineteenth, twentieth,twenty first, twenty second, twenty third, twenty fourth, twenty fifth,thirty fourth, or thirty fifth embodiment.

In a thirty seventh embodiment, for compounds represented by any one ofstructural formulae (II-A1)′, (II-B1)′, (II-C1)′, (II-D1)′, or (II-A2)′,R¹¹ is ethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl,piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl, whereineach substitutable carbon in the morpholinyl, tetrahydro-2H-pyranyl,piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl isoptionally substituted with —OH, halogen, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen inthe piperazinyl is optionally substituted with (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl,—C(═O)(C₁-C₃)alkyl, or —C(═O)H; alternatively, R¹¹ is isopropyl,morpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl,imidazolyl, or oxetanyl, wherein each substitutable carbon in themorpholinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, pyridinyl,imidazolyl, or oxetanyl is optionally substituted with halogen,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutablenitrogen in the piperazinyl is optionally substituted with (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃-C₅)cycloalkyl,—C(═O)(C₁-C₃)alkyl, or —C(═O)H; and values and alternative values forthe remainder of the variables are as described for Structural Formula(I)′, (I-A)′, (II-A0), or in the twenty fourth, twenty fifth, twentysixth, twenty seventh, twenty eighth, twenty ninth, thirtieth, thirtyfirst, or thirty second embodiment.

In a thirty eighth embodiment, for compounds represented by any one ofstructural formulae (I)′, (I), (I-A), (I-A)′, (II-A1)-(II-D),(II-A1)′-(II-D1)′, (II-A2) or (II-A2)′, R^(d) is (C₂-C₇)alkyl or (C₃-C₇)cycloalkyl, wherein both of which are optionally substituted with one ormore groups selected from halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy (preferably, R^(d) is cyclopropyl);and values and alternative values for the remainder of the variables areas described for Structural Formula (I), (I)′, or in the third, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth,fourteenth, fifteenth, sixteenth, twenty third, twenty fourth, twentyfifth, twenty sixth, twenty seventh, twenty eighth, twenty ninth,thirtieth, thirty first, thirty second, thirty third, or thirty seventhembodiment.

In a thirty ninth embodiment, for compounds represented by structuralformula (II-A0), R^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, whereinboth of which are optionally substituted with one or more groupsselected from halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy (preferably, R^(d) is cyclopropyl); and values andalternative values for the remainder of the variables are as describedfor Structural Formula (I-0), (I), (I)′, (I-A), or in the seventeenth,eighteenth, nineteenth, twentieth, twenty first, thirty fourth, orthirty fifth embodiment.

The invention also includes the compounds depicted by structure and/ordescribed by name in the Exemplification, and includes both the neutralforms and as well as pharmaceutically acceptable salts thereof.Treatments with and/or uses of these compounds (including neutral formsand pharmaceutically acceptable salts thereof) as described herein arealso included in the invention.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy”, “haloalkyl”, “cycloalkyl”, “heterocycloalkyl”, “aralkyl”,“heteroaralkyl” and the like, means saturated aliphatic straight-chainor branched monovalent hydrocarbon radical. Unless otherwise specified,an alkyl group typically has 1-6 carbon atoms, i.e., (C₁-C₆)alkyl. Asused herein, a “(C₁-C₆)alkyl” group is means a radical having from 1 to6 carbon atoms in a linear or branched arrangement.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom,represented by —O-alkyl. For example, “(C₁-C₃)alkoxy” includes methoxy,ethoxy, and propoxy.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as thecase may be, substituted with one or more halogen atoms. The term“halogen” means F, Cl, Br or I. Preferably the halogen in a haloalkyl orhaloalkoxy is F or Cl.

The term “ring” used herein means a cyclic group, which includescycloalkyl, heterocycloalkyl, aryl, and heteroaryl. It can bemonocyclic, bicyclic (e.g., a bridged bicyclic ring), polycyclic (e.g.,tricyclic), or fused.

The term “aryl group” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, means an aromatic hydrocarbonring system having six to fourteen carbon ring atoms. The term “aryl”may be used interchangeably with the terms “aryl ring” “aromatic ring”,“aryl group” and “aromatic group”. An aryl group typically has six tofourteen ring atoms. Examples includes phenyl, naphthyl, anthracenyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl and the like. A “substituted aryl group” is substituted at anyone or more substitutable ring atom, which is a ring carbon atom bondedto a hydrogen.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon radicaloptionally containing one or more double bonds. It can be monocyclic,bicyclic (e.g., a bridged bicyclic ring), polycyclic (e.g., tricyclic),or fused. For example, monocyclic (C₃-C₇)cycloalkyl means a radicalhaving from 3-7 carbon atoms arranged in a monocyclic ring. A(C₃-C₇)cycloalkyl includes, but is not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

“Heterocycloalkyl” means a saturated or unsaturated non-aromatic 3-12membered ring radical optionally containing one or more double bonds. Itcan be monocyclic, bicyclic (e.g., a bridged bicyclic ring), tricyclic,or fused. The heterocycloalkyl contains 1 to 4 heteroatoms, which may bethe same or different, selected from N, O or S. The heterocycloalkylring optionally contains one or more double bonds and/or is optionallyfused with one or more aromatic rings (e.g., phenyl ring). “3-7 memberedmonocyclic heterocycloalkyl” means a radical having from 3-7 atoms(including 1-3 heteroatoms) arranged in a monocyclic ring. The term“heterocycloalkyl” is intended to include all the possible isomericforms. Examples of heterocycloalkyl include, but are not limited to,azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl,dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl,dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “heteroaromatic ring”, and “heteroaromatic group”, are usedinterchangeably herein. “Heteroaryl” when used alone or as part of alarger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers toaromatic ring groups having five to fourteen ring atoms selected fromcarbon and at least one (typically 1 to 4, more typically 1 or 2)heteroatoms (e.g., oxygen, nitrogen or sulfur). “Heteroaryl” includesmonocyclic rings and polycyclic rings in which a monocyclicheteroaromatic ring is fused to one or more other aromatic orheteroaromatic rings. As such, “5-14 membered heteroaryl” includesmonocyclic, bicyclic or tricyclic ring systems.

“Monocyclic 5-6 membered heteroaryl” means a monocyclic aromatic ringsystem having five or six ring atoms selected from carbon and at leastone (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen,nitrogen or sulfur). Examples of monocyclic 5-6 membered heteroarylgroups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g.,N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g.,2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl,5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g.,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g.,2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl(e.g., 2-thienyl, 3-thienyl). Examples of polycyclic aromatic heteroarylgroups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,isobenzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl,quinolinyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, orbenzisoxazolyl. A “substituted heteroaryl group” is substituted at anyone or more substitutable ring atom, which is a ring carbon or ringnitrogen atom bonded to a hydrogen.

Unless otherwise indicated, suitable substituents for a substitutedalkyl, cycloalkyl, heterocycloalkyl, aryl group (e.g., phenyl) andheteroaryl group include the groups represented by halogen, —OR^(c),—NR^(a)R^(b), —S(O)_(i)R^(c), —NR^(d1)S(O)_(i)R^(c),—S(O)_(i)NR^(e1)R^(f), —C(═O)OR^(c), —OC(═O)OR^(c), —C(═S)OR^(c),—O(C═S)R^(c), —C(═O)NR^(e1)R^(f), —NR^(d1)C(═O)R^(c),—C(═S)NR^(e1)R^(d), —NR^(d1)C(═S)R^(c), —NR^(d1)(C═O)OR^(c),—O(C═O)NR^(e1)R^(f), —NR^(d1)(C═S)OR^(c), —O(C═S)NR^(e1)R^(f),—NR^(d1)(C═O)NR^(e1)R^(f), —NR^(d1)(C═S)NR^(e1)R^(f), —C(═S)R^(c),—C(═O)R^(c), (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₃)alkyl,heterocycloalkyl, heterocycloalkyl(C₁-C₃)alkyl, aryl, aryl(C₁-C₃)alkyl,heteroaryl and heteroaryl(C₁-C₃)alkyl, wherein:

“cycloalkyl” and “heterocylalkyl” include spiro and as well ascycloalkyl and heterocycloalkyl connected by a single bond to the coreof the molecule.

The term “spiro” refers to a cycloalkyl or heterocycloalkyl that sharesone ring carbon atom with another cycloalkyl or heterocycloalkyl groupin the molecule

R^(a) and R^(b) are each independently selected from —H and(C₁-C₆)alkyl, optionally substituted with 1 to 3 substituentsindependently selected from halogen, hydroxy, —NR^(g)R^(h) and(C₁-C₃)alkoxy;

R^(c) is —H or (C₁-C₆)alkyl, optionally substituted with 1 to 3substituents independently selected from halogen, —NR^(g)R^(h), hydroxyand (C₁-C₃)alkoxy;

R^(d1) is —H or (C₁-C₆)alkyl, optionally substituted with 1 to 3substituents independently selected from halogen, —NR^(g)R^(h), hydroxyand (C₁-C₃)alkoxy;

R^(e1) and R^(f) are each independently selected from —H and(C₁-C₆)alkyl optionally substituted with 1 to 3 substituentsindependently selected from halogen, —NR^(g)R^(h), hydroxy and(C₁-C₃)alkoxy;

or R^(c1) and R^(f), together with the nitrogen to which they areattached, form a 3-8 membered ring optionally substituted with 1 to 3substituents independently selected from halogen, —NR^(g)R^(h), —CN,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₃)alkoxy, halo(C₁-C₃)alkoxy, and(C₁-C₃)alkoxy(C₁-C₆)alkyl;

R^(g) and R^(h) are each independently selected from —H, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and (C₁-C₃)alkoxy(C₁-C₆)alkyl; and

i is 0, 1 or 2;

Unless otherwise indicated, in a preferred embodiment, suitablesubstituents for a substituted alkyl, cycloalkyl, heterocycloalkyl, arylgroup (e.g., phenyl) and heteroaryl group include the groups representedby halogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)hydroxylalkyl, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy, —C(═O)NH₂,—SO₂CH₃, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl (e.g.,—C(═O)(C₃-C₅)cycloalkyl), —C(═O)(C₁-C₃)alkyl, 3-7 membered monocyclicheterocycloalkyl (e.g., oxetanyl).

Unless otherwise indicated, in a preferred embodiment, when phenyl ormonocyclic 5-6 membered heteroaryl is optionally substituted, suitablesubstituents are selected from halogen, hydroxy, CN, amino,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy,—C(═O)NH₂, and —SO₂CH₃.

Unless otherwise indicated, in a preferred embodiment, suitablesubstituents for a substituted alkyl, cycloalkyl, heterocycloalkylinclude halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy and 3-7 membered monocyclic heterocycloalkyl (e.g.,oxetanyl).

Regarding connectivity, an “arylalkyl” moiety, for example, refers to analkyl group substituted with an aryl group (e.g., phenylmethyl (i.e.,benzyl)). Similarly, a “heteroarylalkyl” moiety refers to an alkyl groupsubstituted with a heteroaryl group.

Certain of the compounds described herein may exist in variousstereoisomeric or tautomeric forms. Stereoisomers are compounds whichdiffer only in their spatial arrangement. The present teachingsencompass all such forms, including compounds in the form of essentiallypure enantiomers, racemic mixtures and tautomers, which includes formsnot depicted structurally. When a disclosed compound is named ordepicted by structure without indicating stereochemistry, it isunderstood that the name or structure encompasses all possiblestereoisomers, tautomers, geometric isomers or a combination thereof.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the geometric isomeric purity of the named or depictedgeometric isomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure byweight. Geometric isomeric purity is determined by dividing the weightof the named or depicted geometric isomer in the mixture by the totalweight of all of the geometric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. The present teachings encompass all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures, and diastereomeric mixtures of thecompounds described herein.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers are included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein. The disclosed compounds have basicamine groups and therefore can form pharmaceutically acceptable saltswith pharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds described herein includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, nitric, and sulfuric acids) and of organic acids (such as,acetic acid, benzenesulfonic, benzoic, methanesulfonic, andp-toluenesulfonic acids). Compounds of the present teachings with acidicgroups such as carboxylic acids can form pharmaceutically acceptablesalts with pharmaceutically acceptable base(s). Suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts) and alkaline earthmetal salts (such as magnesium and calcium salts). Compounds with aquaternary ammonium group also contain a counteranion such as chloride,bromide, iodide, acetate, perchlorate and the like. Other examples ofsuch salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, benzoates and salts with amino acids suchas glutamic acid.

Compounds described herein can inhibit various kinases, including theTTK. Thus, generally, compounds described herein are useful in thetreatment of diseases or conditions associated with such kinases. Insome embodiments, compounds described herein can inhibit TTK.

In one embodiment, the compounds described herein are TTK inhibitors,and are useful for treating diseases, such as cancer, associated withsuch kinase(s).

Another aspect of the present teachings relates to a method of treatinga subject with cancer comprising administering to the subject aneffective amount of a compound described herein. In one embodiment, thecompounds described herein inhibit the growth of a tumor. For example,the compounds described herein inhibit the growth of a tumor thatoverexpresses TTK.

Cancers that can be treated (including reduction in the likelihood ofrecurrence) by the methods of the present teachings include lung cancer,breast cancer, colon cancer, brain cancer, neuroblastoma, prostatecancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma,leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma,glioma and mesothelioma. In one embodiment, the cancer is selected fromleukemia, acute myeloid leukemia, chronic myelogenous leukemia, breastcancer, brain cancer, colon cancer, colorectal cancer, head and neckcancer, hepatocellular carcinoma, lung adenocarcinoma, metastaticmelanoma, pancreatic cancer, prostate cancer, ovarian cancer and renalcancer. In one embodiment, the cancer is lung cancer, colon cancer,brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastomamultiform or ovarian cancer. In another embodiment, the cancer ispancreatic cancer, prostate cancer, lung cancer, melanoma, breastcancer, colon cancer, or ovarian cancer. In yet another embodiment, thecancer is breast cancer, colon cancer and ovarian cancer. In yet anotherembodiment, the cancer is a breast cancer. In yet another embodiment,the cancer is a basal sub-type breast cancer or a luminal B sub-typebreast cancer. In yet another embodiment, the cancer is a basal sub-typebreast cancer that overexpresses TTK. In yet another embodiment, thebasal sub-type breast cancer is ER (estrogen receptor), HER2 and PR(progesterone receptor) negative breast cancer. In yet anotherembodiment, the cancer is a soft tissue cancer. A “soft tissue cancer”is an art-recognized term that encompasses tumors derived from any softtissue of the body. Such soft tissue connects, supports, or surroundsvarious structures and organs of the body, including, but not limitedto, smooth muscle, skeletal muscle, tendons, fibrous tissues, fattytissue, blood and lymph vessels, perivascular tissue, nerves,mesenchymal cells and synovial tissues. Thus, soft tissue cancers can beof fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels,lymph vessels, and fibrous tissues. Soft tissue cancers can be benign ormalignant. Generally, malignant soft tissue cancers are referred to assarcomas, or soft tissue sarcomas. There are many types of soft tissuetumors, including lipoma, lipoblastoma, hibernoma, liposarcoma,leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma,schwannoma (neurilemoma), neuroma, malignant schwannoma,neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovialsarcoma, hemangioma, glomus tumor, hemangiopericytoma,hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma,fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma,fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP),malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor,malignant mesenchymomas, alveolar soft-part sarcoma, epithelioidsarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In aparticular embodiment, the soft tissue cancer is a sarcoma selected fromthe group consisting of a fibrosarcoma, a gastrointestinal sarcoma, aleiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphicliposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, anda synovial sarcoma.

In some embodiments, the present teachings provide methods of inhibitingthe growth of tumor-initiating cells or reducing the likelihood ofrecurrence of a cancer in a subject who is undergoing an anti-cancertherapy. The method comprises the steps of:

a) assessing the subject to determine whether the cancer is inremission; and

b) if the cancer is in remission; then administering to the subject aneffective amount of a TTK inhibitor (e.g., a compound represented byStructural Formula (I-0), (I) or (I)′). If the cancer is not inremission, the method optionally further comprises the step ofcontinuing the anti-cancer therapy until the cancer goes into remissionand then the step b) of administering an effective amount of a TTKinhibitor (e.g., a compound represented by Structural Formula (I-0), (I)or (I)′).

As used herein, the term “tumor-initiating cells” or “TICs” refer tocells present within some tumors that possess the ability to self-renewand proliferate. These cells are sometimes called cancer stem cells(CSCs) and may be observed to share certain characteristics with normalstem cells, including a stem cell-like phenotype and function. In someembodiments, TICs are characterized by their ability to form tumorsafter xenotransplantation in immunodeficient mice.

In some embodiments, the present teachings provide methods of inhibitingthe growth of tumor-initiating cells or reducing the likelihood ofrecurrence of a cancer in a subject whose cancer is in remissioncomprising administering to the subject an effective amount of a TTKinhibitor (e.g, a compound represented by Structural Formula (I-0), (I)or (I)′).

In some embodiments, e.g., where the subject is being treated to reducethe likelihood of recurrence of a cancer, the subject has already beentreated with an anti-cancer therapy. Alternatively, the subject hasalready been treated with an anti-cancer therapy and the subject is inremission.

In some embodiments, the present teachings provide methods of treating asubject with a cancer comprising administering to the subject aneffective amount of a compound represented by Structural Formula (I-0),(I) or (I)′ in combination with an effective anti-cancer therapy. In oneembodiment, the cancer is a metastatic cancer. A “metastatic cancer” isa cancer that has spread from its primary site to other parts of thebody.

In another embodiment, the present teachings are directed to a method oftreating a subject with a drug-resistant cancer. A “drug-resistantcancer” is a cancer that is not responsive to one, two, three, four,five or more drugs that are typically used for the treatment of thecancer. In one embodiment, the drug-resistant cancer is mediated by thegrowth of tumor-initiating cells.

Suitable methods known in the art can be used for assessing a subject todetermine whether the cancer is in remission. For example, the size ofthe tumor and/or tumor markers, usually proteins associated with tumors,can be monitored to determine the state of the cancer. Size of the tumorcan be monitored with imaging devices, such as X-ray, MRI, CAT scans,ultrasound, mammography, PET and the like or via biopsy.

For methods described herein, e.g., coadministration methods, theanti-cancer therapy are selected from the group consisting of surgery,radiation therapy, immunotherapy, endocrine therapy, gene therapy andadministration of an anti-cancer agent. Alternatively, the anti-cancertherapy is radiation therapy. In another alternative, the anti-cancertherapy is immunotherapy. In another alternative, the anti-cancertherapy is administration of an anti-cancer agent. In yet anotheralternative, the anti-cancer therapy is surgery.

Radiation therapy is the use of radiation to kill, destroy or treat thecancers. Exemplary radiation therapy includes, but is not limited to,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and radioisotope therapy (i.e., systemicradioactive isotopes therapy),

An endocrine therapy is a treatment that adds, blocks or removeshormones. For example, chemotherapeutic agents that can block theproduction or activity of estrogen have been used for treating breastcancer. In addition, hormonal stimulation of the immune system has beenused to treat specific cancers, such as renal cell carcinoma andmelanoma. In one embodiment, the endocrine therapy comprisesadministration of natural hormones, synthetic hormones or othersynthetic molecules that may block or increase the production of thebody's natural hormones. In another embodiment, the endocrine therapyincludes removal of a gland that makes a certain hormone.

As use herein, a gene therapy is the insertion of genes into a subject'scell and biological tissues to treat diseases, such as cancer. Exemplarygene therapy includes, but is not limited to, a germ line gene therapyand a somatic gene therapy.

Immunotherapy (also called biological response modifier therapy,biologic therapy, biotherapy, immune therapy, or biological therapy) istreatment that uses parts of the immune system to fight disease.Immunotherapy can help the immune system recognize cancer cells, orenhance a response against cancer cells. Immunotherapies include activeand passive immunotherapies. Active immunotherapies stimulate the body'sown immune system while passive immunotherapies generally use immunesystem components created outside of the body.

Examples of active immunotherapies include, but are not limited tovaccines including cancer vaccines, tumor cell vaccines (autologous orallogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotypevaccines, DNA vaccines, viral vaccines, or Tumor-Infiltrating Lymphocyte(TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine-Activated Killer(LAK) Cell Therapy.

Examples of passive immunotherapies include but are not limited tomonoclonal antibodies and targeted therapies containing toxins.Monoclonal antibodies include naked antibodies and conjugated monoclonalantibodies (also called tagged, labeled, or loaded antibodies). Nakedmonoclonal antibodies do not have a drug or radioactive materialattached whereas conjugated monoclonal antibodies are joined to, forexample, a chemotherapy drug (chemolabeled), a radioactive particle(radiolabeled), or a toxin (immunotoxin). Examples of these nakedmonoclonal antibody drugs include, but are not limited to Rituximab(Rituxan), an antibody against the CD20 antigen used to treat, forexample, B cell non-Hodgkin lymphoma; Trastuzumab (Herceptin), anantibody against the HER2 protein used to treat, for example, advancedbreast cancer; Alemtuzumab (Campath), an antibody against the CD52antigen used to treat, for example, B cell chronic lymphocytic leukemia(B-CLL); Cetuximab (Erbitux), an antibody against the EGFR protein used,for example, in combination with irinotecan to treat, for example,advanced colorectal cancer and head and neck cancers; and Bevacizumab(Avastin) which is an antiangiogenesis therapy that works against theVEGF protein and is used, for example, in combination with chemotherapyto treat, for example, metastatic colorectal cancer. Examples of theconjugated monoclonal antibodies include, but are not limited toRadiolabeled antibody Ibritumomab tiuxetan (Zevalin) which deliversradioactivity directly to cancerous B lymphocytes and is used to treat,for example, B cell non-Hodgkin lymphoma; radiolabeled antibodyTositumomab (Bexxar) which is used to treat, for example, certain typesof non-Hodgkin lymphoma; and immunotoxin Gemtuzumab ozogamicin(Mylotarg) which contains calicheamicin and is used to treat, forexample, acute myelogenous leukemia (AML). BL22 is a conjugatedmonoclonal antibody for treating, for example, hairy cell leukemia,immunotoxins for treating, for example, leukemias, lymphomas, and braintumors, and radiolabeled antibodies such as OncoScint for example, forcolorectal and ovarian cancers and ProstaScint for example, for prostatecancers.

Further examples of therapeutic antibodies that can be used include, butare not limited to, HERCEPTIN® (Trastuzumab) (Genentech, CA) which is ahumanized anti-HER2 monoclonal antibody for the treatment of patientswith metastatic breast cancer; REOPRO® (abciximab) (Centocor) which isan anti-glycoprotein IIb/IIIa receptor on the platelets for theprevention of clot formation; ZENAPAX® (daclizumab) (RochePharmaceuticals, Switzerland) which is an immunosuppressive, humanizedanti-CD25 monoclonal antibody for the prevention of acute renalallograft rejection; PANOREX™ which is a murine anti-17-IA cell surfaceantigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2 which is a murineanti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™which is a humanized anti-αVβ3 integrin antibody (Applied MolecularEvolution/MedImmune); Campath 1H/LDP-03 which is a humanized anti CD52IgG1 antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgGantibody (Protein Design Lab/Kanebo); RITUXAN™ which is a chimericanti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku);LYMPHOCIDE™ which is a humanized anti-CD22 IgG antibody (Immunomedics);LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled;radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs);CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is aprimatied anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN™ is aradiolabelled murine anti-CD20 antibody (IDEC/Schering AG); IDEC-131 isa humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primatizedanti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody(IDEC/Scikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (ProteinDesign Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody(Alexion Pharm); D2E7 is a humanized anti-TNF-α antibody (CAT/BASF);CDP870 is a humanized anti-TNF-α Fab fragment (Celltech); IDEC-151 is aprimatized anti-CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham);MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab);CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanizedanti-TNF-α IgG4 antibody (Celltech); LDP-02 is a humanized anti-α4β7antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4IgG antibody (Ortho Biotech); ANTOVA™ is a humanized anti-CD40L IgGantibody (Biogen); ANTEGREN™ is a humanized anti-VLA-4 IgG antibody(Elan); and CAT-152 is a human anti-TGF-β₂ antibody (Cambridge Ab Tech).

Immunotherapies that can be used in the present teachings includeadjuvant immunotherapies. Examples include cytokines, such asgranulocyte-macrophage colony-stimulating factor (GM-CSF),granulocyte-colony stimulating factor (G-CSF), macrophage inflammatoryprotein (MIP)-1-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6,IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors(including TNF-alpha), and interferons (including IFN-alpha, IFN-beta,and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guérin(BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant(IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), andcombinations thereof, such as, for example, combinations of,interleukins, for example, IL-2 with other cytokines, such as IFN-alpha.

Alternatively, the anti-cancer therapy described herein includesadministration of an anti-cancer agent. An “anti-cancer agent” is acompound, which when administered in an effective amount to a subjectwith cancer, can achieve, partially or substantially, one or more of thefollowing: arresting the growth, reducing the extent of a cancer (e.g.,reducing size of a tumor), inhibiting the growth rate of a cancer, andameliorating or improving a clinical symptom or indicator associatedwith a cancer (such as tissue or serum components) or increasinglongevity of the subject.

The anti-cancer agent suitable for use in the methods described hereinincludes any anti-cancer agents that have been approved for thetreatment of cancer. In one embodiment, the anti-cancer agent includes,but is not limited to, a targeted antibody, an angiogenesis inhibitor,an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, apodophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplasticagent and other antineoplastic agents.

Examples of alkylating agents useful in the methods of the presentteachings include but are not limited to, nitrogen mustards (e.g.,mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.),ethylenimine and methylmelamines (e.g., hexamethylmelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomustine, semustine, streptozocin, etc.), or triazenes (decarbazine,etc.). Examples of antimetabolites useful in the methods of the presentteachings include but are not limited to folic acid analog (e.g.,methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine,Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine,pentostatin). Examples of plant alkaloids and terpenoids or derivativesthereof include, but are not limited to, vinca alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine), podophyllotoxin, andtaxanes (e.g., paclitaxel, docetaxel). Examples of a topoisomeraseinhibitor include, but are not limited to, irinotecan, topotecan,amsacrine, etoposide, etoposide phosphate and teniposide. Examples ofantineoplastic agents include, but are not limited to, actinomycin,anthracyclines (e.g., doxorubicin, daunorubicin, valrubicin, idarubicin,epirubicin), bleomycin, plicamycin and mitomycin.

In one embodiment, the anti-cancer agents that can be used in thepresent teachings include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-1 a; interferongamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Yet other anti-cancer agents/drugs that can be used in the presentteachings include, but are not limited to: 20-epi-1,25 dihydroxyvitaminD3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; rasinhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred additional anti-cancer drugs are 5-fluorouraciland leucovorin.

In one embodiment, the anti-cancer agents that can be used in methodsdescribed herein are selected from the group consisting of paclitaxel,docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab,letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine,capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin,doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine,vincristine, melphalan and a combination thereof.

In one embodiment, the anti-cancer agent and the compound represented byStructural Formula (I-0), (I) or (I)′ are administeredcontemporaneously. When administered contemporaneously, the anti-canceragent and the compound can be administered in the same formulation or indifferent formulations. Alternatively, the compound and the additionalanti-cancer agent are administered separately. Alternatively, thecompound and the additional anti-cancer agent can be administeredsequentially, as separate compositions, within an appropriate time frame(e.g., a cancer treatment session/interval (e.g., about 1.5 to about 5hours to about 10 hours to about 15 hours to about 20 hours; about 1 dayto about 2 days to about 5 days to about 10 days to about 14 days)) asdetermined by the skilled clinician (e.g., a time sufficient to allow anoverlap of the pharmaceutical effects of the therapies). The compoundand the additional anti-cancer agent can be administered in a singledose or multiple doses in an order and on a schedule suitable to achievea desired therapeutic effect (e.g., inhibition of tumor growth).

In one embodiment, the subject in the methods described herein has notbeen previously treated with a TTK inhibitor (e.g., the compoundrepresented by Structural Formula (I-0), (I) or (I)′).

The term “inhibiting the growth of tumor-initiating cells” refers todecreasing the rate of the proliferation and/or survival of thetumor-initiating cells.

As used herein, the term “reducing the likelihood of recurrence of acancer” means partially or totally inhibiting, delaying the return of acancer at or near a primary site and/or at a secondary site after aperiod of remission. It also means that the cancer is less likely toreturn with treatment described herein than in its absence.

As used herein, the term “remission” refers to a state of cancer,wherein the clinical symptoms or indicators associated with a cancerhave disappeared or cannot be detected, typically after the subject hasbeen successfully treated with an anti-cancer therapy.

As used herein, “treatment” is an approach for obtaining beneficial ordesired results, including clinical results. Beneficial or desiredclinical results can include, but are not limited to, alleviation oramelioration of one or more symptoms or conditions, diminishment ofextent of disease, stabilized (i.e., not worsening) state of disease,reducing the likelihood of the spread of the disease, delay or slowingof disease progression, amelioration or palliation of the disease state,whether detectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.“Treatment” also includes reducing the likelihood of reoccurrence of thedisease.

As used herein, “treating a subject with a cancer” includes achieving,partially or substantially, one or more of the following: arresting thegrowth, reducing the extent of the cancer (e.g., reducing size of atumor), inhibiting the growth rate of the cancer, ameliorating orimproving a clinical symptom or indicator associated with the cancer(such as tissue or serum components) or increasing longevity of thesubject; and reducing the likelihood of recurrence of the cancer.

Generally, an effective amount of a compound taught herein variesdepending upon various factors, such as the given drug or compound, thepharmaceutical formulation, the route of administration, the type ofdisease or disorder, the identity of the subject or host being treated,and the like, but can nevertheless be routinely determined by oneskilled in the art. An effective amount of a compound of the presentteachings may be readily determined by one of ordinary skill by routinemethods known in the art.

The term an “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the cancer(e.g., as determined by clinical symptoms or the amount of cancer cells)in a subject as compared to a control.

In an embodiment, an effective amount of a compound taught herein rangesfrom about 0.1 to about 1000 mg/kg body weight, alternatively about 1 toabout 500 mg/kg body weight, and in another alternative, from about 20to about 300 mg/kg body weight. In another embodiment, an effectiveamount of a compound taught herein ranges from about 0.5 to about 5000mg/m², alternatively about from 5 to about 2500 mg/m², and in anotheralternative from about 50 to about 1000 mg/m². The skilled artisan willappreciate that certain factors may influence the dosage required toeffectively treat a subject suffering from cancer or reduce thelikelihood of recurrence of a cancer. These factors include, but are notlimited to, the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject and otherdiseases present.

Moreover, for methods described herein (including treating a subjectwith a cancer or reducing the likelihood of recurrence of a cancer), a“treatment” or dosing regimen of a subject with an effective amount ofthe compound of the present teachings may consist of a singleadministration, or alternatively comprise a series of applications. Forexample, the compound of the present teachings may be administered atleast once a week. However, in another embodiment, the compound may beadministered to the subject from about one time per week to once dailyfor a given treatment. The length of the treatment period depends on avariety of factors, such as the severity of the disease, the age of thepatient, the concentration and the activity of the compounds of thepresent teachings, or a combination thereof. It will also be appreciatedthat the effective dosage of the compound used for the treatment mayincrease or decrease over the course of a particular treatment regime.Changes in dosage may result and become apparent by standard diagnosticassays known in the art. In some instances, chronic administration maybe required.

A “subject” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

The compounds taught herein can be administered to a patient in avariety of forms depending on the selected route of administration, aswill be understood by those skilled in the art. The compounds of thepresent teachings may be administered, for example, by oral, parenteral,buccal, sublingual, nasal, rectal, patch, pump or transdermaladministration and the pharmaceutical compositions formulatedaccordingly. Parenteral administration includes intravenous,intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal,intrapulmonary, intrathecal, rectal and topical modes of administration.Parenteral administration can be by continuous infusion over a selectedperiod of time.

The compounds taught herein can be suitably formulated intopharmaceutical compositions for administration to a subject. Thepharmaceutical compositions of the present teachings optionally includeone or more pharmaceutically acceptable carriers and/or diluentstherefor, such as lactose, starch, cellulose and dextrose. Otherexcipients, such as flavoring agents; sweeteners; and preservatives,such as methyl, ethyl, propyl and butyl parabens, can also be included.More complete listings of suitable excipients can be found in theHandbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press(2005)). A person skilled in the art would know how to prepareformulations suitable for various types of administration routes.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003-20th edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredientsof the pharmaceutical composition and not deleterious to the recipientthereof.

Typically, for oral therapeutic administration, a compound of thepresent teachings may be incorporated with excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

Typically for parenteral administration, solutions of a compound of thepresent teachings can generally be prepared in water suitably mixed witha surfactant such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, DMSO and mixturesthereof with or without alcohol, and in oils. Under ordinary conditionsof storage and use, these preparations contain a preservative to preventthe growth of microorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound described herein for theextemporaneous preparation of sterile injectable solutions ordispersions are appropriate.

For nasal administration, the compounds of the present teachings can beformulated as aerosols, drops, gels and powders. Aerosol formulationstypically comprise a solution or fine suspension of the active substancein a physiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively, the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant which can be a compressed gassuch as compressed air or an organic propellant such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

For buccal or sublingual administration, the compounds of the presentteachings can be formulated with a carrier such as sugar, acacia,tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.

For rectal administration, the compounds described herein can beformulated in the form of suppositories containing a conventionalsuppository base such as cocoa butter.

The compounds of invention may be prepared by methods known to thoseskilled in the art, as illustrated by the general schemes and proceduresbelow and by the preparative examples that follow. All startingmaterials are either commercially available or prepared by methods knownto those skilled in the art and the procedures described below.

In accordance with another aspect of the present invention, thecompounds of the invention can be prepared by processes analogues tothose established in the art. General methods to synthesize the claimedcompounds are elaborated below in Example A.

EXEMPLIFICATION Example A: Synthesis

General Methods

Commercially available starting materials, reagents, and solvents wereused as received. In general, anhydrous reactions were performed underan inert atmosphere such as nitrogen or Argon. PoraPak® Rxn CX refers toa commercial cation-exchange resin available from Waters. Microwavereactions were performed with a Biotage Initiator microwave reactor.Reaction progress was generally monitored by TLC using Merck silica gelplates with visualization by UV at 254 nm, by analytical HPLC or by LCMS(Bruker Exquire 4000 or Waters Acquity UPLC system). Flash columnchromatographic purification of intermediates or final products wasperformed using 230-400 mesh silica gel 60 from EMD chemicals orSilicycle, or purified using a Biotage Isolera with KP-SIL or HP-SILsilica cartridges, or KP-NH basic modified silica and correspondingsamples. Reverse-phase HPLC purification was performed on a VarianPrepStar model SD-1 HPLC system with a Varian Monochrom 10 u C-18reverse-phase column using a of about 5-30% MeCN or MeOH/0.05% TFA-H₂Oto 70-90% MeCN or MeOH/0.05% TFA in H₂O over a 20-40-min period at aflow rate of 30-80 mL/min. Reverse phase purification was also performedusing a Biotage Isolera equipped with a KP-C18-H column using a between10-95% MeOH or CH₃CN/0.1% TFA in H₂O. Proton NMRs were recorded on aBruker 400 MHz spectrometer, and mass spectra were obtained using aBruker Esquire 4000 spectrometer or Waters Acquity UPLC system.

Compound names were generated using the software built intoCambridgeSoft-PerkinElmer's ChemBioDraw Ultra version 11.0 or 12.0.

Abbreviations:

Ac Acetyl

aq aqueous

anh anhydrous

Ar argon

BINOL 1,1′-binaphthalene-2,2′-diol

Boc tert-butoxycarbonyl

br. broad

calcd calculated

d doublet (only when used within 1H NMR spectra)

d day

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-dichloroethane

DCC N,N′-dicyclohexylcarbodiimide

DCM dichloromethane

DEA diethylamine

de diastereomeric excess

DIPEA diisopropylethylamine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

dppf 1,1′-bis(diphenylphosphino) ferrocene

h hour

hal halogen

HPLC high performance liquid chromatography

IPA iso-propanol

LC-MS liquid chromatography coupled to mass spectrometry

min minute

m multiplet

mCPBA meta-chloroperoxybenzoic acid

MS ESI mass spectra, electrospray ionization

NMR nuclear magnetic resonance

NBS N-Bromosuccinimide

O/N overnight

pin pinacol

PMB para-methoxybenzyl

prep preparative

PTSA para-toluenesulfonic acid

RBF round bottomed flask

rt room temperature

Rt retention time

RP reverse phase

s singlet

satd saturated

SMs starting materials

S_(N)Ar Nucleophilic Aromatic Substitution

SPE solid phase extraction

t triplet

TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

TEA triethylamine

temp. temperature TFA trifluoroacetic acid

TLC thin layer chromatography

THF tetrahydrofuran

THP tetrahydropyranyl

xs excess

By way of illustration, pyrazolotriazine compounds of Structural Formula6 may be prepared by the methods outlined in Scheme 1. Treatment of8-halo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine 1 withsuitably substituted aliphatic primary amine or alcohol in the presenceof base such as DIPEA, TEA, pyridine and DBU yields the desiredintermediate 2. In the case where primary amine is used in the previousstep, protection of the nitrogen is performed using standard procedureswell known in the art before the Suzuki-Miyaura cross coupling reaction.A detailed description of techniques applicable to the creation ofprotecting groups and their removal can be found in T. W. Green,“Protecting Groups in Organic Chemistry”, 3^(rd) edition, John Wiley andSons, Inc., 1999. The subsequent Suzuki-Miyaura cross coupling iscarried out in the presence of a Pd catalyst (e.g. PdCl₂(dppf) orPd(PPh₃)₄), and a suitably substituted aryl boronate ester or boronicacid and a base (e.g. aq K₃PO₄, or Na₂CO₃) at high temperatures (e.g.100-130° C.). Removal of protecting group under acidic conditions (e.g.for PG=PMB at TFA, 35-80° C.) followed by oxidation of methylsulfideusing oxidants (e.g. mCPBA) afforded the desired intermediate 5. Thecompounds of the invention 6 can be synthesized via an nucleophilicaromatic substitution in the presence of primary/secondary amines oralcohols/phenols in the presence of a suitable base (e.g. DIPEA, TEA,DBU, NaH), at a temperature in the range of rt to 80° C.

Alternatively, final compound 6 can be synthesized using the reactionsequence depicted in Scheme 2 where intermediate 4 undergoes anoxidation of methylsulfide followed by nucleophilic aromaticsubstitution and removal of protecting group using the reactionconditions described above.

The starting materials of formula I can be synthesized using proceduresanalogues to those well known in the arts of heterocyclic and organicchemistry for the production of structurally analogous compounds. Thus,intermediate 7 is synthesized according to a procedure fromInternational Patent Application Publication No. WO2011/079231. Desiredintermediate 1 can be obtained by bromination of intermediate 7 usingNBS or other brominating reagents.

Compounds described herein can be prepared in a manner analogous to thegeneral procedures described above or the detailed procedures describedin the examples herein.

Pyrazolopyrimidine compounds of the present invention may be prepared bythe methods outlined in Scheme 4.

General Method a (Amination)

To a cooled (0° C.) DCM solution (0.1-1 M) of3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 equiv) or8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.0equiv) was added primary amine (1-2 equiv) and DIPEA or TEA (1-2 equiv).Alternatively, primary amine (2-3 equiv) was added alone withoutDIPEA/TEA. The reaction was stirred at rt for 0.5-24 h. The product waspartitioned between EtOAc or DCM and satd NaHCO₃ solution, dried overNa₂SO₄ or MgSO₄, filtered, and concentrated to dryness. In the majorityof examples the crude product was used without further purification oralternatively the material was purified by flash chromatography.

General Method B (Boc Protection)

To a solution of pyrazolo[1,5-a]pyrimidin-7-amine derivative (1 equiv)in DCM was added Boc₂O (0.8-1.5 equiv), followed by DMAP (0.1-0.2 equiv)and Et₃N (1-2 equiv). The resulting mixture was stirred at rt andpurified by flash chromatography (gradient: EtOAc/hex 0-100%).

General Method B2 (PMB Protection)

A solution of8-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1 equiv) inDMF (0.2-1M), 4-methoxybenzyl chloride (1.0-1.2 equiv), and K₂CO₃ (2equiv) was heated to 60° C. for 2-4 h. The product was partitionedbetween EtOAc and H₂O, dried over Na₂SO₄ or MgSO₄, filtered,concentrated to dryness, and purified by flash chromatography.

General Method C (Nucleophilic Substitutions of Amines)

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine(1.0 equiv) in THF, dioxane, DME, DMF or NMP was added amines oramine-HCl (1-2 equiv) and DIPEA (1-3 equiv). The resulting mixture wasstirred at rt for 24 h or more generally the reaction was heated in amicrowave reactor, an oil bath or a reaction block at temperatures from35-130° C. for 2-12 h. Solvent was removed in vacuo and the crudeproduct was purified by flash chromatography.

Alternatively, a solution of pyrazolo[1,5-a]pyrimidin-5-chlorinederivative (1 equiv) or2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0equiv) and amine or aniline (2-22 equiv) was heated in a microwavereactor, an oil bath or a reaction block at temperatures from 35-170° C.for 2-12 h. Solvent was removed in vacuo and the crude product waspurified by flash chromatography.

General Method D (Nucleophilic Substitutions of Alcohols)

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1equiv) or 2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine(1.0 equiv) and alcohol (1-3 equiv) in DMF or THF at 0° C. was added 60%NaH (1.5-6 equiv). The resulting mixture was stirred at rt for 1-4 h.After cooling to 0° C., quenching with satd NH₄Cl and H₂O, it wasextracted with EtOAc and purified by flash chromatography.

General Method E (Nucleophilic Substitutions of Phenols orHydroxylpyridine)

Using phenol and K₂CO₃:

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1equiv) and phenol (2-3 equiv) in DMF was added K₂CO₃ (3 equiv). Theresulting mixture was stirred O/N at rt and quenched with H₂O. Theprecipitates were collected by suction filtration and dried to give thedesired product. Alternatively, the aqueous layer was extracted withEtOAc. The organic layer was dried (Na₂SO₄ or MgSO₄), filtered,concentrated to dryness and purified by flash chromatography.

Using Phenol and DBU:

A mixture of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv) or2-(methylsulfonyl)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0equiv) in DME or DMF, phenol (2-4 equiv), and DBU (2-4 equiv) was heatedin a microwave reactor, an oil bath or a reaction block at temperatures80-100° C. for 1-4 h. Solvent was removed and the crude product waspurified by flash chromatography.

Using Phenoxide:

To a solution of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1equiv) in DMF was added sodium phenoxides (1-1.5 equiv, commercial orfreshly made using phenols and NaOH in H₂O). The resulting mixture wasstirred at rt for 30 min to O/N and quenched with H₂O. The precipitateswere collected by suction filtration and dried to give the desiredproduct. Alternatively the aqueous layer was extracted with EtOAc. Theorganic layer was dried (Na₂SO₄ or MgSO₄), filtered, concentrated todryness and purified by flash chromatography.

General Method F (Suzuki-Miyaura Coupling; Followed by Boc or PMBDeprotection if Applicable)

A mixture of pyrazolo[1,5-a]pyrimidin-3-bromine derivative (1.0 equiv)or8-bromo-N-(4-methoxybenzyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine(1.0 equiv), boronic acid or aryl boronate ester (1-3 equiv), aq K₃PO₄(1-2 M, 3-5 equiv) and PdCl₂dppfDCM (0.05-0.2 equiv) in THF was heatedunder Ar in a microwave reactor, an oil bath or a reaction block attemperatures 80-130° C. for 2 h to 2 days. The product was partitionedbetween EtOAc and H₂O, dried over Na₂SO₄ or MgSO₄, filtered andconcentrated to dryness, then purified by flash chromatography.

If Boc deprotection is required, the above compound was redissolved inDCM and treated with TFA and stirred O/N. After removal of TFA, it wastriturated with MeOH or purified by flash chromatography or prep-HPLC.

Alternatively, the Boc deprotection can be done in microwave in mixtureof H₂O and DMF or NMP or EtOH at 100-140° C. for 1-4 h and purified byprep-HPLC, reversed phase or normal phase Biotage column.

For PMB deprotection: A solution ofN-(4-methoxybenzyl)-2-(methylthio)-8-arylpyrazolo[1,5-a][1,3,5]triazin-4-amine(1 equiv) in a mixture of DCM and TFA (2:1 v/v) or DCE and TFA (3:1 v/v)was heated in a microwave reactor, an oil bath or a reaction block attemperatures 60-100° C. for 30 min-30 h. Solvent was removed in vacuoand the crude product was purified by chromatography.

General Method G (Borylation of Aryl Halides): Using B₂pin₂/Pd

A mixture of aryliodide or arylbromide (1 equiv), B₂pin₂ (1.2 to 1.5equiv), KOAc (3 equiv.) and DMF or DMSO was purged with Ar for 10 min.PdCl₂(dppf).DCM (3-5 mol %) was added, the vial sealed and heated at80-100° C. for 2-6 h. The product was partitioned between EtOAc and satdaq NaHCO₃, washed with brine, dried over Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness. The crude product was purified by flashchromatography to give the title compound.

General Method H (Substitution with Sodium Sulfinate)

A mixture of pyrazolo[1,5-a]pyrimidin-5-chlorine derivative (1 equiv)and sodium sulfinate (1-1.2 equiv) in DMF was heated at 60° C. in oilbath or microwave for 1-2 h. After removal of solvents, it was purifiedby flash chromatography on SiO₂.

General Method I (Suzuki on Pyrazolo[1,5-a]Pyrimidin-5-PhenylsulphonylDerivative)

To a mixture of the pyrazolo[1,5-a]pyrimidin-5-phenylsulphonylderivative (1 equiv) andN-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(1-1.5 equiv) in THF was added 2 M K₃PO₄ (3 equiv), followed byPdCl₂dppfDCM (2-10 mol %). The resulting mixture was purged with Ar andthen heated at 60° C. for 1.5 h to O/N. It was diluted with brine,extracted with EtOAc and combined. After removal of solvents, theresidue was purified by flash chromatography on SiO₂.

General Method J (Nucleophilic Substitutions on Benzenesulfonate,Followed by Boc Deprotection)

To a solution of pyrazolo[1,5-a]pyrimidin-5-phenylsulphonyl derivative(1 equiv, 0.05-0.3 M) in DMF or NMP was added amines, amine-HCls (1-3equiv) and DIPEA (1-3 equiv) or phenolates (prepared from NaOH andphenols in H2O, after drying). The resulting mixture was heated inmicrowave at 100-130° C. for 1-6 h.

For the Boc deprotection, after adding 0.5-2 volumes of H₂O, theresulting mixture was heated in microwave at 120-140° C. for 1-4 h andpurified by prep-HPLC or reversed phase Biotage column.

Intermediates:

Synthesis of 4-bromo-N-cyclopropyl-2-methylbenzamide

To a suspension of 4-bromo-2-methylbenzoic acid (43.0 g, 200 mmol) andoxalyl dichloride (30.5 g, 240 mmol) in DCM (300 mL) was added DMF (0.1mL). The resulting reaction mixture was stirred at rt for 16 h. Thereaction turned into a clear yellow solution slowly over 16 h. Solventwas then removed in vacuo, and the crude product was used in the nextstep without further purification. The crude product was redissolved inDCM (300 mL) and cooled to 0° C. A mixture of TEA (42 mL, 300 mmol) andcyclopropylamine (12.6 g, 220 mmol) in DCM (100 mL) was added slowlyover 15 min, and the resulting mixture was stirred at rt for 2 h. Thereaction was diluted with DCM (200 mL) and water was added. Theresulting mixture was extracted with DCM and the combined organicextracts were dried over MgSO₄ and concentrated to give the desiredproduct as a pale pink solid (50.1 g, 99%). ¹H NMR (400 MHz, CDCl₃) δppm 7.37 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 5.93(br, s, 1H), 2.90-2.85 (m, 1H), 2.40 (s, 3H), 0.90-0.85 (m, 2H),0.62-0.58 (m, 2H); MS ESI [M+H]⁺ 253.9, calcd for [C₁₁H₁₂BrNO+H]⁺ 254.0.

Synthesis of N-(4-bromo-2-methylphenyl)cyclopropanecarboxamide

In a 100 mL RBF, 4-bromo-2-methylaniline (3.7 g, 20 mmol) and DIPEA(6.95 mL, 40 mmol) were combined with DMF (40 mL). The reaction wascooled to 0° C. in an ice bath and cyclopropanecarbonyl chloride (2.1 g,20 mmol) was added. The mixture was stirred at 0° C. for 1 h. Water andEtOAc were added to separate the phases and the aqueous phase wasextracted with EtOAc. The organic layers were combined, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give thetitle compound as a white solid (4.76 g, 94%). ¹H NMR (400 MHz, CDCl₃) δppm 7.85-7.72 (m, 1H), 7.38-7.28 (m, 2H), 7.15-7.02 (m, 1H), 2.27 (s,3H), 1.57-1.48 (m, 1H), 1.10 (quint, J=3.9 Hz, 2H), 0.92-0.79 (m, 2H);MS ESI [M+H]⁺ 253.9, calcd for [C₁₁H₁₂BrNO+H]⁺ 254.0.

Synthesis ofN-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a mixture of 4-bromo-N-cyclopropyl-2-methylbenzamide (3.73 g, 14mmol), Bis(pinacolato)diboron (5.59 g, 22 mmol), anh KOAc (4.29 g, 43mmol) in DMF (37 mL) was purged with Ar for 10 min at rt. ThenPdCl₂(dppf).DCM (0.59 g, 5 mol %) was added and the reaction was heatedat 100° C. in oil bath for 4 h. After reaction completion the reactionmass was diluted with EtOAc (200 mL) & H₂O (100 mL). The combined layerfiltered through celite pad and washed it with little EtOAc. The aq.layer further extracted with EtOAc (50 mL) and the combined organiclayer washed with brine, dried over Na₂SO₄, filtered, and concentratedto give crude oily residue. The crude product was purified by flashchromatography (gradient: EtOAc/hex 0-100%) to give the title compoundas a creamy solid (4.15 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.66 (s,1H), 7.63-7.61 (d, J=7.6 Hz, 1H), 7.32-7.30 (d, J=7.6 Hz, 1H), 5.85 (s,1H), 2.93-2.87 (m, 1H), 2.46 (s, 3H), 1.35 (s, 12H), 0.90-0.86 (m, 2H),0.63-0.59 (m, 2H); MS ESI [M+H]⁺ 302.2, calcd for [C₁₇H₂₄BNO₃+H]⁺ 302.2.

The following compounds were synthesized according to the synthesis ofGeneral Method G

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]+ Saltform N-(2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl) cyclopropanecarboxamide

[C₁₇H₂₄BNO₃ + H]⁺ 302.2; 302.4 1.13 g (63%); white solid; free base SMs:N-(4-bromo-2-methylphenyl)cyclopropanecarboxamide (1.5 g, 5.9 mmol),(PinB)₂ (2.3 g, 8.9 mmol), PdCl₂dppf DCM (242 mg, 0.30 mmol). ¹H NMR(400 MHz, CDCl3) δ ppm 8.03 (br, s, 1H), 7.70-7.60 (m, 2H), 7.36-7.29(m, 1H), 2.31 (s, 3 H), 1.58-1.48 (m, 1H), 1.34 (s, 12 H), 1.15-1.05 (m,2H), 0.90-0.80 (m, 2H).

Synthesis of (cis)-4-hydroxy-N-(4-methoxybenzyl)cyclohexanecarboxamide

TBTU (3.21 g, 10.0 mmol) was added in one portion to a stirred DMF(anh., 20 mL) solution of (cis)-4-hydroxycyclohexanecarboxylic acid(1.44 g, 9.9 mmol), 4-methoxybenzylamine (1.37 g, 9.9 mmol) and DIPEA(1.8 mL, 10.3 mmol) at rt. Stirring was continued for 21 h, then thereaction was diluted with H₂O and taken into EtOAc (150 mL). The organicphase was washed with H₂O (50 mL and 30 mL). The aq. phases werecombined, concentrated under reduced pressure and purified by RP HPLC(C18, MeOH—H₂O) to afford the title compound as a white solid (0.83 g,32%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.21 (d, J=8.28 Hz, 2H), 6.88 (d,J=8.28 Hz, 2H), 5.69 (br. s., 1H), 4.39 (d, J=5.52 Hz, 2H), 4.01 (br.s., 1H), 3.81 (s, 3H), 2.12-2.26 (m, 1H), 1.78-1.97 (m, 4H), 1.76-1.66(m, 2H), 1.65-1.57 (m, 2H); MS ESI [M+H]⁺ 264.2, calcd for[C₁₅H₂₁NO₃+H]⁺ 264.15.

Synthesis of (cis)-4-(((4-methoxybenzyl)amino)methyl)cyclohexanol

LiAlH₄ (1.0 M in THF, 10.0 mL, 10 mmol) was added slowly to an anh THF(40 mL) solution of (cis)-4-hydroxy-N-(4-methoxybenzyl)cyclohexanecarboxamide (0.83 g, 3.1 mmol) at 0° C. Stirring wascontinued with cooling for another 5 min, later the reaction was allowedto warm to rt and subsequently heated at 60° C. overnight. The reactionwas cooled to rt and poured carefully to a stirred cold (0° C.) mixtureof xs Na₂SO₄.10H₂O in DCM. The reaction was stirred for additional 2 hat rt and then filtered under vacuum. The solid was rinsed with DCM andthe filtrate was concentrated under reduced pressure to give the desiredmaterial that was used without further purification (pale yellow oil,0.79 g, quant). MS ESI [M+H]⁺ 250.3, calcd for [C₁₅H₂₃NO₂+H]⁺ 250.18.

Synthesis of8-bromo-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

The title compound was synthesized according to General Method Autilizing 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine(1.5 g, 5.4 mmol), 4-(aminomethyl)tetrahydro-2H-pyran hydrochloride(0.81 g, 534 mmol), and DIPEA (1.9 mL, 11 mmol) at 0° C.-rt for 1 h. Thedesired product was isolated as a beige solid (1.8 g, 95%) and was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (s,1H), 6.53 (br s, 1H), 4.01 (dd, J=11.3, 3.6 Hz, 2H), 3.58 (t, J=6.6 Hz,2H), 3.41 (t, J=11.8 Hz, 2H), 2.61 (s, 3H), 1.94-2.00 (m, 1H), 1.68-1.73(m, 2H), 1.38-1.49 (m, 2H); MS ESI [M+H]⁺ 358.2, calcd for[C₁₂H₆BrN₅OS+H]⁺ 358.03.

Synthesis of (1r,4r)-4-(((4-methoxybenzyl)amino)methylcyclohexanol

A sealed vial charged with (1r,4r)-4-hydroxycyclohexanecarboxylic acid(0.505 g, 3.20 mmol), (4-methoxyphenyl)methanamine (0.460 g, 3.35 mmol),1H-1,2,4-triazole (44 mg, 0.2 mmol), DBU (0.100 g. 0.66 mmol) was heatedwith stirring at 70° C. for 3 d. The reaction was directly loaded a SiO₂column and purified by flash chromatography (gradient: EtOAc/hex 0-30%)to afford (1r,4r)-4-hydroxy-N-(4-methoxybenzyl)-cyclohexanecarboxamide(705 mg, 84%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.19 (d,J=8.3 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.28 (s, 2H), 3.77 (s, 3H),3.57-3.46 (m, 1H), 2.20-2.09 (m, 1H), 2.05-1.94 (m, 2H), 1.90-1.80 (m,2H), 1.62-1.49 (m, 2H), 1.33-1.19 (m, 2H); MS ESI [M+H]⁺ 264.2, calcdfor [C₁₂H₂₁NO₃+H]⁺ 264.1.

A solution of the above(1r,4r)-4-hydroxy-N-(4-methoxybenzyl)cyclohexanecarboxamide (0.705 g,2.7 mmol) in anh THF (30 mL) was treated with LiAlH₄ (1 M in THF, 8 mL,8 mmol) at rt and then heated at reflux O/N under Ar. The reactionmixture was cooled to rt and added slowly to a stirred suspension of xsNa₂SO₄.10H₂O in DCM at 0° C. The reaction was stirred for 2 h thenfiltered and concentrated to provide the title compound (0.67 g,quantitative) as pale orange gum used without further purification. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.25 (d, J=8.53 Hz, 2H), 6.92-6.85 (d, J=8.8Hz, 2H), 3.78 (s, 3H), 3.68 (s, 2H), 3.61-3.54 (m, 1H), 3.51-3.40 (m,1H), 2.40 (d, J=6.8 Hz, 2H), 1.99-1.90 (m, 2H), 1.88-1.74 (m, 2H),1.63-1.58 (m, 1H), 1.52-1.41 (m, 1H), 1.35-1.15 (m, 2H), 1.08-0.85 (m,2H); MS ESI [M+H]⁺ 250.2, calcd for [C₁₂H₂₃NO₂+H]⁺ 250.2.

Synthesis of 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine

To a stirred solution of sodium ethoxide in EtOH, which was preparedfrom sodium (281.3 g, 12.0 mol) and EtOH (10 L) by the conventionalmethod, were added diethyl malonate (963.7 g, 6.02 mol) at ambienttemperature and then compound 1H-pyrazol-3-amine (500 g, 6.02 mol). Thereaction mixture was refluxed for 12 hours. After cooled to roomtemperature, the precipitates were collected by filtration and dissolvedin water. The aqueous solution was acidified with 2 M HCl (pH=2). Theresulting precipitates were collected by filtration and dried underreduced pressure to afford pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione(649 g, 71%) as a yellow solid, which was used for the next reactionwithout further purification.

A stirred suspension of pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (265g, 1.75 mol) and N,N-dimethylaniline (335.6 mL) in POCl₃ (2.00 kg, 13.2mol) was refluxed for 4 hours. After cooled to room temperature, thereaction mixture was poured into ice-water, and stirred for 30 min,neutralized with saturated aqueous sodium carbonate and extracted withEtOAc. The combined organic layers were washed with water, brine anddried over MgSO₄, filtered and evaporated. The residue was purified bycolumn chromatography on silica gel (gradient: EtOAc/PE 1:10) to give5,7-dichloropyrazolo[1,5-a]pyrimidine (287 g, 87%) as a yellow solid.

To a solution 5,7-dichloropyrazolo[1,5-a]pyrimidine (246.6 g, 1.31 mol)in CH₃CN (1.8 L) was added NBS (245 g, 1.38 mol). The resulting mixturewas stirred at room temperature for 2 hours. After removal of thesolution, the reaction mixture was purified by column chromatography onsilica gel (gradient: EtOAc/PE 1:5) to give the title compound (313.5 g,89%) as light yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 7.04 (s, 1H),8.21 (s, 1H); MS ESI [M+H]⁺ 265.9, calcd for [C₆H₂BrCl₂N₃+H]⁺ 265.9.

Synthesis of3-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

To a solution of 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g,10 mmol) in DCM (30 mL) at 0° C. was added(tetrahydro-2H-pyran-4-yl)methan-amine (1.27 g, 11 mmol), followed byDIPEA (2.1 mL, 12 mmol). The resulting mixture was stirred at rt for hand purified by flash chromatography (gradient: EtOAc/hex 0-90%) to givethe title compound as white solid (3.46 g, quantitative yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 6.55-6.43 (m, 1H), 6.00 (s, 1H),4.08-4.00 (m, 2H), 3.43 (dt, J=12.0, 1.7 Hz, 2H), 3.32 (t, J=6.6 Hz,2H), 2.06-1.94 (m, 1H), 1.78-1.71 (m, 2H), 1.51-1.38 (m, 2H); MS ESI[M+H]⁺ 345.1, calcd for [C₁₂H₁₄BrCN₄O+H]⁺ 344.9.

The following intermediates were synthesized according to General MethodA:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform 8-bromo-2-(methylthio)-N-(2- morpholinoethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

[C₁₂H₁₇BrN₆ OS + H]⁺ 373.0; 372.8 1.108 g (88%); white solid; free baseSMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (945mmol, 3.37 mmol), 2- morpholinoethanamine (0.47 ml, 3.61 mmol). ¹H NMR(400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.05 (s, 1H), 3.85-3.65 (m, 6H),2.75-2.55 (m, 9H). 8-bromo-2-(methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine

[C₁₃H₁₉BrN₆ OS + H]⁺ 387.1; 387.1 3.47 g (100%); white solid; free baseSMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (2.5g, 8..94 mmol), 3- morpholinopropan-1-amine (1.31 mL, 8.94 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 9.11 (br. s., 1 H), 7.85 (d, J = 0.8 Hz, 1 H),3.90 (t, J = 4.5 Hz, 4 H), 3.72-3.80 (m, 2 H), 2.58-2.66 (m, 5 H), 2.54(br. s., 4 H), 1.80-1.91 (m, 2 H). (cis)-4-(((8-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)(4- methoxybenzyl)amino)methyl)cyclohexanol

[C₂₁H₂₆BrN₅ O₂S + H]⁺ 492.1; 492.1 0.39 g (64%); white foam; free baseSMs: 8-bromo-4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine(0.343 g, 1.23 mmol), (cis)-4-(((4-methoxybenzyl)amino)methyl)cyclohexanol (0.31 g, 1.24 mmol), DIPEA(0.22 mL, 1.24 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (s, 1 H), 7.18(d, J = 8.28 Hz, 2 H), 6.85 (d, J = 8.53 Hz, 2 H), 5.01-5.62 (br.s. 2H),4.01 (br. s., 1 H), 3.65-3.98 (br.s, 2H), 3.80 (s, 3 H), 2.57 (s, 3 H),1.85-1.99 (m, 1 H), 1.69-1.80 (m, 2 H), 1.42-1.67 (m, 6 H).3-bromo-5-chloro-N-(2- methoxyethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₉H₁₀BrClN₄O + H]⁺ 305.0; 304.9 2.94 (96%); white solid; free base SMs:3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g, 10 mmol),2-methoxyethanamine (1.9 mL, 21 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm7.98 (s, 1H), 6.70 (br, s, 1H), 6.02 (s, 1H), 3.69 (t, J = 5.2 Hz, 2H),3.58 (t, J = 5.2 Hz, 2H), 3.44 (s, 3H). 3-bromo-5-chloro-N-(2-morpholinoethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₂H₁₅BrCl N₅O + H]⁺ 360.0; 359.9 3.21 g (89%); white solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (2.67 g, 10 mmol),2-morpholinoethanamine (1.45 mL, 11 mmol), DIPEA (2.1 mL, 12 mmol). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.02-7.08 (m, 1H), 5.97 (s,1H), 3.77 (t, J = 4.6 Hz, 2H), 3.47-3.42 (m, 4H), 2.77 (t, J = 5.8 Hz,2H), 2.55 (t, J = 4.2 Hz, 4H). 3-bromo-5-chloro-N-(3-morpholinopropyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₃H₁₇BrCl N₅O + H]⁺ 376.0; 376.0 530 mg (75%); white solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.873 mmol),3-morpholinopropan- 1-amine (540 mg, 3.745 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.97 (br, s, 1H), 7.97 (s, 1H), 5.93 (s, 1H), 3.92 (t, J =4.6 Hz, 4H), 3.56-3.40 (m, 2H), 2.69-2.61 (m, 2H), 2.55 (br, s, 4H),2.00-1.87 (m, 2H). 3-bromo-5-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₃H₁₆BrCl N₄O + H]⁺ 361.0; 361.1 662 mg (98%); white solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.873 mmol),2-(tetrahydro-2H- pyran-4-yl)ethanamine (266 mg, 2.06 mmol), DIPEA (0.37mL, 2.25 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 6.34 (br, s,1H), 5.99 (s, 1H), 4.00 (dd, J = 11.2, 4.4 Hz, 2H), 3.52-3.34 (m, 4H),1.77-1.63 (m, 5H), 1.48-1.33 (m, 2H). 3-bromo-5-chloro-N-isobutylpyrazolo[1,5-a]pyrimidin-7- amine

[C₁₀H₁₂BrCl N₄ + H]⁺ 303.0; 303.0 1.10 g (96%); clear oil; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 g, 3.8 mmol),isobutylamine (304 mg, 4.2 mmol), DIPEA (1.44 mL, 8.34 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 6.47 (br, s, 1H), 5.99 (s, 1H),3.26-3.16 (m, 2H), 2.12-1.98 (m, 1H), 1.07 (d, J = 6.5 Hz 6H).1-((3-bromo-5-chloropyrazolo[1,5- a]pyrimidin-7-yl)amino)-2-methylpropan-2-ol

[C₁₀H₁₂BrCl N₄O + H]⁺ 319.0; 319.0 910 mg (76%); white solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (1 g, 3.8 mmol),1-amino-2-methylpropan-2-ol (371 mg, 4.2 mmol), DIPEA (1.3 mL, 7.56mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1 H), 6.80 (br, s, 1H),6.04 (s, 1H), 3.36 (d, J = 6.0 Hz, 2H), 1.61 (s, 1H), 1.39 (s, 6H).(1r,4r)-4-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)(4-methoxybenzyl)amin)methyl) cyclohexanol

[C₂₁H₂₄BrCl N₄O₂ + H]⁺ 479.1/481.1; 479.0/481.0 0.36 g (84%); whitesolid; free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (239g, 0.89 mmol), (1r,4r)-4-(((4- methoxybenzyl)amino)methyl)cyclohexanol(223 mg, 0.89 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.01 (s, 1H), 7.12(d, J = 8.28 Hz, 2H), 6.86 (d, J = 8.53 Hz, 2 H), 6.02 (s, 1H), 5.05 (s,2H), 3.80 (s, 3H), 3.59 (d, J = 6.78 Hz, 2H), 3.57-3.46 (m, 1H,2.02-1.91 (m, 2H), 1.84-1.70 (m, 2H),1.37 (d, J = 4.52 Hz, 1H),1.31-1.15 (m, 2H), 1.05-0.90 (m, 2H). 3-bromo-5-chloro-N-(cyclopropylmethyl)pyrazolo[1,5- a]pyrimidin-7-amine

[C₁₀H₁₀BrCl N₄ + H]⁺ 301.0; 301.0 5.3 g (92%); yellow solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.0 g, 19 mmol),cyclopropylmethanamine (1.5 g, 21 mmol), and DIPEA (6.6 mL, 38 mmol). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 6.50 (br. s, 1H), 5.97 (s, 1H),3.25 (dd, J = 7.3, 5.5 Hz, 2H), 1.26-1.13 (m, 1H), 0.74-0.65 (m, 2H),0.37 (q, J = 5.0 Hz, 2H). (1s,3s)-3-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)amino)methyl)-1- methylcyclobutanol

[C₁₂H₁₄BrCl N₄O + H]⁺ 345.0; 345.1 6.1 g (94%); yellow solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.0 g, 19 mmol),cis-hydroxy-3- methylcyclobutane-1-methylamine (2.4 g, 21 mmol), andDIPEA (6.6 mL, 38 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H),6.60-6.49 (m, 1H), 5.99 (s, 1H), 3.47 (t, J = 6.0 Hz, 2H), 2.38-2.27 (m,3H), 1.96-1.85 (m, 2H), 1.43 (s, 3H). tert-butyl 4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)amino)methyl)-4-fluoropiperidine-1-carboxylate

[C₁₇H₂₂BrClFN₂ O₂ + H]⁺ 462.1; 462.1 6.0 g (100%); yellow solid; freebase SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (3.45 g, 12.9mmol), tert-butyl 4- (aminomethyl)-4-fluoropiperidine-1-carboxylate (3.0g, 12.9 mmol), and DIPEA (4.5 mL, 25.8 mmol). ¹H NMR (400 MHz, CDCl₃) δppm 8.00 (s, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.19-3.93 (m, 2H), 3.58(d, J = 6.5 Hz, 1H), 3.53 (d, J = 6.5 Hz, 1H), 3.10 (br. s., 2H),2.04-1.90 (m, 2H), 1.77-1.62 (m, 2H), 1.48 (s, 9H).(R)-3-bromo-5-chloro-N- ((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₁H₁₂BrClN₄ O + H]⁺ 331.0; 330.9 13.6 g (91.3%); light yellow solid;free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (12 g, 45mmol), (R)-(tetrahydrofuran-3- yl)methanamine (5 g, 49.5 mmol), DIPEA(8.9 mL, 54 mmol), DCM (150 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s,1H), 6.57 (br. s., 1 H), 6.02 (s, 1H), 4.01 (td, J = 8.4, 5.3 Hz, 1 H),3.87 (dd, J = 9.2, 6.7 Hz, 1H), 3.84-3.77 (m, 1H), 3.73 (dd, J = 9.0,4.3 Hz, 1H), 3.44-3.39 (m, 2H), 2.77-2.65 (m, 1H), 2.29-2.15 (m, 1H),1.80-1.69 (m, 1H). (S)-3-bromo-5-chloro-N- ((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₁H₁₂BrClN₄ O + H]⁺ 331.0; 331.1 8.05 g (92.5%); light yellow solid;free base SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (7 g, 26mmol) (S)-(tetrahydrofuran-3- yl)methanamine (2.92 g, 28 mmol), DIPEA(5.71 mL, 32 mmol), DCM (56 mL). ¹H NMR identical to (R)-isomer3-bromo-5-chloro-N-((1- methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyrimidin- 7-amine

[C₁₃H₁₇BrCl N₅ + H]⁺ 358.0; 358.0 0.534 g, (78%); pale yellow foam; freebase SMs: (1-methylpiperidin-4-yl)methanamine (0.247 g, 1.9 mmol),3-bromo-5,7-dichloropyrazolo[1,5- a]pyrimidine (0.516 g, 1.9 mmol) ¹HNMR (400 MHz, CDCl₃) δ ppm 7.91 (s, 1H), 6.58 (t, J = 5.9 Hz, 1H), 5.95(s, 1H), 3.30 (t, J = 6.40 Hz, 2H), 2.99 (d, J = 11.8 Hz, 2H), 2.35 (s,3H), 2.08 (td, J = 11.9, 2.0 Hz, 2H), 1.86-1.79 (m, 2H), 1.79-1.67 (m,1H), 1.58-1.47 (m, 2H) 3-bromo-5-chloro-N-(2-(4- fluoropiperidin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7- amine

[C₁₃H₁₆BrClF N₅ + H]⁺ 376.0; 376.1 0.79 g, (68%); pale solid; free baseSMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (0.92 g, 3.4 mmol),2-(4-fluoropiperidin-1- yl)ethanamine (0.46 g, 3.1 mmol) ¹H NMR (400MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.08 (br. s., 1H), 5.97 (s, 1H),5.05-4.52 (m, 1H), 3.47-3.36 (m, 2H), 2.82-2.72 (m, 2H), 2.72-2.58 (m,2H), 2.57-2.43 (m, 2H), 2.05-1.86 (m, 4H)

Synthesis of8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

The title compound was synthesized according to General Method B2utilizing8-bromo-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.8 g, 5.1 mmol), 4-methoxybenzyl chloride (0.83 mL,6.1 mmol), K₂CO₃ (1.4 g, 10.1 mmol) and DMF (14 mL) at 60° C. for 4 h.The crude product was purified by flash chromatography (SiO₂, 0-50%EtOAc/DCM) to give the desired product as a white solid (2.2 g, 89%). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.84 (s, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.86(d, J=8.8 Hz, 2H), 5.31 (br. s., 2H), 3.96 (dd, J=11.7, 2.9 Hz, 3H),3.73-3.86 (m, 3H), 3.25-3.41 (m, 2H), 2.57 (s, 3H), 2.01-2.20 (m, 1H),1.57-1.61 (m, 3H), 1.32-1.47 (m, 2H); MS ESI [M+H]⁺ 480.3, calcd for[C₂₀H₂₄BrN₅O₂S+H]⁺ 480.08.

Synthesis of tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of3-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.46 g, 10 mmol) in DCM (40 mL) was addedBoc₂O (1.91 g, 8.8 mmol), followed by Et₃N (1.7 mL, 12 mmol) and DMAP(122 mg, 1 mmol). The resulting mixture was stirred at rt for 2 h.Additional Boc₂O (348 mg, 1.6 mmol) and Et₃N (0.28 mL, 2 mmol) wereadded and the mixture was stirred at rt for 1 h. After removal ofsolvents, it was purified by flash chromatography (gradient: EtOAc/hex0-50%) to give the title compound as pale yellow foam (4.51 g,quantitative) after drying. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H),6.75 (s, 1H), 3.96-3.86 (m, 2H), 3.71 (d, J=6.8 Hz, 2H), 3.29 (t, J=11.4Hz, 2H), 1.85-1.73 (m, 1H), 1.67-1.58 (m, 2H), 1.45-1.25 (m, 11H; s, 9Hat 1.34); MS ESI [M+H]⁺ 445.0, calcd for [C₁₇H₂₂BrClN₄O₃+H]⁺ 445.1.

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform 8-bromo-N-(4-methoxy benzyl)-2- (methylthio)-N-(2-morpholinoethyl)pyrazolo[1,5-a][1,3,5]triazin-4- amine

[C₂₀H₂₅BrN₆ O₂S + H]⁺ 493.1; 493.7 1.10 g (75%); colorless oil; freebase SMs:8-bromo-2-(methylthio)-N-(2-morpholinoethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine(1.010 g, 3 mmol), 4-methoxybenzyl chloride (0.5 ml, 3.6 mmol). ¹H NMR(400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.85 (d, J= 8.8 Hz, 2H), 5.35-5.10 (m, 2H), 4.10-3.90 (m, 2H), 3.69 (s, 3H),3.47-3.35 (m, 7H), 2.54 (t, J = 6.4 Hz, 2H), 2.37- 2.26 (m, 4H).8-bromo-N-(4-methoxybenzyl)-2- (methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5- a][1,3,5]triazin-4-amine

[C₂₁H₂₇BrN₆ O₂S + H]⁺ 507.1; 507.8 3.25 g (84%); white solid; free baseSMs:8-bromo-2-(methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine(2.95 g, 7.64 mmol), 4-methoxybenzyl chloride (1.27 mL, 9.17 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 6.87(d, J = 8.5 Hz, 2 H), 5.06-5.47 (br, s, 2 H), 3.98 (br. s., 2 H), 3.81(s, 3 H), 3.70 (d, J = 4.3 Hz, 4 H), 2.57 (s, 3 H), 2.31- 2.45 (m, 6 H),1.83-1.94 (m, 2 H).

The following intermediates were synthesized according to General MethodB2:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate

[C₁₄H₁₈BrCl N₄O₃ + H]⁺ 405.0; 404.9 4.98 g (90%); light yellow solid;free base SMs:3-bromo-5-chloro-N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidin-7-amine(4.19 g, 13.7 mmol) Boc₂O (2.89 g, 13.3 mmol), DMAP (171 mg, 1.4 mmol).¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.95 (s, 1H), 3.96 (t, J =5.0 Hz, 2H), 3.59 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 1.37 (s, 9H).tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate

[C₁₇H₂₃BrCl N₅O₃ + H]⁺ 460.0; 460.8 3.59 g (88%); off white solid; freebase SMS:3-bromo-5-chloro-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidin-7-amine(3.21 g, 8.9 mmol), Boc₂O (1.91 g, 8.8 mmol), DMAP (110 mg, 0.9 mmol).¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (s, 1H), 6.90 (s, 1H), 3.94 (t, J =5.6 Hz, 2H), 3.30-3.22 (m, 4H), 2.54 (t, J = 5.6 Hz, 2H), 2.24 (t, J =4.4 Hz, 4H), 1.36 (s, 9H). tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₁₈H₂₅BrCl N₅O₃ + H]⁺ 474.1; 474.9 626 mg (94%); pale yellow solid;free base SMs:3-bromo-5-chloro-N-(3-morpholinopropyl)pyrazolo[1,5-a]pyrimidin-7-amine(530 mg, 1.41 mmol). Boc₂O (368 mg, 2.11 mmol), DMAP (17 mg, 0.14 mmol),Et₃N (0.24 mL, 1.69 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H),7.27 (s, 1H), 6.83 (s, 1H), 3.88 (t, J = 7.3 Hz, 2H), 3.59 (t, J = 4.4Hz, 4H), 2.34 (t, J = 6.9 Hz, 2H), 2.30-2.24 (m, 3H), 1.81 (quint, J =7.2 Hz, 2H), 1.38 (s, 9H). tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₁₈H₂₄BrCl N₄O₃ + H]⁺ 459.0; 459.3 800 mg (95%); yellow solid; freebase SMS:3-bromo-5-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine(662 mg, 1.83 mmol), Boc₂O (480 mg, 2.21mmol), DMAP (22 mg, 0.18 mmol),Et₃N (0.3 mL, 2.2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1H),6.76 (s, 1H), 3.93 (dd, J = 11.2, 3.6 Hz, 2H), 3.88- 3.81 (m, 2 H), 3.34(t, J = 11.0 Hz, 2H), 1.62-1.47 (m, 5H), 1.38 (s, 9H), 1.34-1.21 (m,2H). tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate

[C₁₅H₂₀BrCl N₄O₂ + H]⁺ 403.0; 403.0 1.19 g (81%); white solid; free baseSMs: 3-bromo-5-chloro-N-isobutylpyrazolo[1,5-a]pyrimidin-7-amine (1.10g, 3.64 mmol), Boc₂O (869 mg, 4.01 mmol), DMAP (44 mg, 0.36 mmol), TEA(0.61 mL, 4.37 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (s, 1 H), 6.76(s, 1H), 3.65 (d, J = 7.3 Hz, 2H), 1.87-1.75 (m, 1H), 1.36 (s, 9H), 0.91(d, J = 6.8 Hz, 6H). tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin- 7-yl)(2-((tert- butoxycarbonyl)oxy)-2-methylpropyl)carbamate

[C₂₀H₂₈BrCl N₄O₅ + H]⁺ 519.0; 519.0 809 mg (67%); white solid; free baseSMs:1-((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)-2-methylpropan-2-ol(744 mg, 2.34 mmol), Boc₂O (869 mg, 4.01 mmol), DMAP (44 mg, 0.36 mmol),TEA (0.65 mL, 4.67 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H),6.83 (s, 1H), 4.06 (s, 2H), 1.56 (s, 6H), 1.33 (s, 9H), 1.22 (s, 9H).tert-butyl (3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7-yl)(cyclopropylmethyl)carbamate

[C₁₅H₁₈BrCl N₄O₂ − C₄H₈]⁺ 345.0; 345.0 6.24 g (89%); yellow solid; freebase SMs:3-bromo-5-chloro-N-(cyclopropylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine(5.25 g, 17.5 mmol), Boc₂O (5.70 g, 26.2 mmol), DMAP (0.21 g, 1.75mmol), and TEA (7.3 mL, 52.5 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12(s, 1H), 6.85 (s, 1H), 3.72 (d, J = 7.3 Hz, 2H), 1.39 (s, 9H), 1.05-0.94(m, 1H), 0.46-0.37 (m, 2 H) 0.13-0.03 (m, 2 H). tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate

[C₂₂H₃₀BrCl N₄O₅ + H]⁺ 545.1; 545.1 0.90 g (40%); white solid; free baseSMS:(1s,3s)-3-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-1-methylcyclobutanol (1.44 g, 4.2 mmol), Boc₂O (2.2 g, 10.5 mmol), DMAP(0.10 g, 0.84 mmol), and TEA (1.75 mL, 12.6 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.11 (s, 1H), 6.74 (s, 1H), 3.88 (d, J = 6.5 Hz, 2H), 2.17(s, 3H), 1.99-1.88 (m, 2H), 1.47 (s, 3H), 1.45 (s, 9H), 1.35 (s, 9H).tert-butyl 4-(((3-bromo-5- chloropyrazolo[1,5-a]pyrimidin- 7-yl)(tert-butoxycarbonyl)amino)methyl)-4- fluoropiperidine-1-carboxylate

[C₂₂H₃₀BrClF N₅O₄ + H]⁺ 508.1; 508.1 7.0 g (97%); yellow solid; freebase SMs: tert-butyl4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-4-fluoropiperidine-1-carboxylate (6.0 g, 12.9 mmol), Boc₂O (4.36 g, 20.0mmol), DMAP (0.33 g, 2.66 mmol), and DIPEA (4.7 mL, 26.6 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.12 (s, 1H), 6.84 (s, 1H), 4.14-3.84 (m, 4H),3.09-2.88 (m, 2H), 2.02-1.86 (m, 2H), 1.79-1.61 (m, 2H), 1.47 (s, 9H),1.33 (s, 9H). (R)-tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydrofuran-3-yl)methyl)carbamate

[C₁₆H₂₀BrCl N₄O₃ + H − Boc]⁺ 331.0; 330.9 16.16 g (91%); light yellowsolid; free base SMs:(R)-3-bromo-5-chloro-N-((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine(13.6 g, 41.1 mmol), Boc₂O (10.75 g, 49.3 mmol), DMAP (501 mg, 4.11mmol), Et₃N (6.87 mL, 49.3 mmol), DCM (100 mL). ¹H NMR (400 MHz, CDCl₃)δ ppm 8.13 (s, 1H), 6.77 (s, 1H), 3.91-3.80 (m, 3H), 3.79-3.67 (m, 2H),3.48 (dd, J = 8.8, 5.5 Hz, 1H), 2.53-2.40 (m, 1H), 2.02-1.90 (m, 1H),1.65-1.54 (m, 1H), 1.36 (s, 9H). (S)-tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydrofuran-3-yl)methyl)carbamate

[C₁₆H₂₀BrCl N₄O₃ + H − Boc]⁺ 331.0; 331.1 9.8 g (92.5%); yellow solid;free base SMs:(S)-3-bromo-5-chloro-N-((tetrahydrofuran-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine(8.05 g, 24.2 mmol), Boc₂O (5.56 g, 25.4 mmol), DMAP (295 mg, 2.4 mmol),Et₃N (4.39 mL, 31.4 mmol). ¹H NMR identical to (R)-isomer tert-butyl(3-bromo-5- chloropyrazolo[1,5-a]pyrimidin-7- yl)((1-methylpiperidin-4-yl)methyl)carbamate

[C₁₈H₂₅BrCl N₅O₂ + H]⁺ 458.1; 458.1 0.483 g (70%); pale yellow solid;free base Sms:3-bromo-5-chloro-N-((1-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine(0.534 g, 1.5 mmol), Boc₂O (0.37 g, 1.7 mmol) ¹H NMR (400 MHz, CD₃OD) δppm 8.24 (s, 1H), 7.22 (s, 1H), 3.74 (d, J = 7.3 Hz, 2H), 2.91-2.84 (m,2H), 2.27 (s, 3H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.63-1.49 (m,1H), 1.32 (s, 9H), 1.31- 1.17 (m, 2H) tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7- yl)(2-(4-fluoropiperidin-1-yl)ethyl)carbamate

[C₁₈H₂₄BrClF N₅O₂ + H]⁺ 476.1; 476.1 1.0 g (quant.); pale foam; freebase SMs:3-bromo-5-chloro-N-(2-(4-fluoropiperidin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine(0.79 g, 2.1 mmol), Boc₂O (0.91 g, 4.2 mmol) ¹H NMR (400 MHz, CDCl₃) δppm 8.10 (s, 1H), 6.93 (s, 1H), 4.65-4.37 (m, 1H), 3.94 (t, J = 5.6 Hz,2H), 2.55 (t, J = 5.6 Hz, 2H), 2.45-2.32 (m, 2H), 2.30-2.14 (m, 2H),1.59-1.45 (m, 2H), 1.46-1.29 (m, 2H), 1.37 (s, 9H)

Synthesis ofN-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method Futilizing8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine(550 mg, 1.15 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(520 mg, 1.73 mmol), aq K₃PO₄ (2.0 mL, 4.0 mmol) and PdCl₂dppfDCM (94mg, 0.110 mmol) at 130° C. for 4 h. The crude product was purified byflash chromatography (SiO₂, 10-40% EtOAc/DCM) to give the desiredproduct as a yellow solid (600 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ ppm8.21 (s, 1H), 7.81-7.93 (m, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.92 (br. s., 1H), 5.15-5.62 (m, 2H),3.97 (dd, J=11.4, 2.9 Hz, 3H), 3.80 (s, 3H), 3.35 (t, J=10.8 Hz, 2H),2.92 (td, J=7.0, 3.1 Hz, 1H), 2.61 (s, 3H), 2.53 (s, 3H), 2.08-2.23 (m,1H), 1.57-1.61 (m, 3H), 1.34-1.49 (m, 2H), 0.85-0.93 (m, 2H), 0.56-0.68(m, 2H); MS ESI [M+H]⁺ 573.5, calcd for [C₃₁H₃₆N₆O₃S+H]⁺ 573.26.

Synthesis of tert-butyl(3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate(446 mg, 1 mmol) and cyclopentamine (0.11 mL, 1.1 mmol, 1.1 equiv) inTHF (6 mL) was added DIPEA (0.22 mL, 1.2 mmol, 1.2 equiv). The resultingmixture was microwaved 3 h at 80° C., 1 h at 120° C. and 1 h at 130° C.The reaction was then allowed to cool to room temperature and wasdiluted with EtOAc and water was added. The resulting mixture wasextracted with EtOAc and the combined organic extracts were dried overMgSO₄ and concentrated to give the crude product. Crude product waspurified by flash chromatography (gradient: EtOAc/hex 5-40%) to give thetitle compound as a pale yellow solid (420 mg, 85%). NMR ¹H NMR (400MHz, CDCl3) δ ppm 7.81 (s, 1H), 5.96 (s, 1H), 5.01 (br, s, 1H),4.43-4.15 (m, 1H), 3.95 (d, J=7.5 Hz, 2H), 3.63 (d, J=7.0 Hz, 2H),3.43-3.20 (m, 2H), 2.21-2.08 (m, 2H), 1.88-1.60 (m, 7H), 1.56-1.49 (m,2H), 1.33-1.23 (m, 2H); MS ESI [M+H]⁺ 494.9, calcd for [C₂₂H₃₂BrN₅O₃+H]⁺494.2.

The following intermediates were synthesized according to General MethodC:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform tert-butyl (3-bromo-5-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₁H₃₂BrN₅ O₄ + H]⁺ 498.2; 498.8 810 mg (81%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (891 mg, 2 mmol), 1-amino-2-methylpropan-2-ol (356 mg, 2mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s, 1H), 6.01 (s, 1H),5.32-5.37 (m, 1H), 3.97-3.92 (m, 2H), 3.63 (d, J = 7.2 Hz, 2H), 3.55 (d,J = 5.6 Hz, 2H), 3.33 (t, J = 10.2 Hz, 2H), 1.87-1.75 (m, 1H), 1.69-1.62 (m, 2H), 1.37 (s, 9H), 1.33 (s, 6H), 1.31-1.26 (m, 2H). tert-butyl(3-bromo-5- morpholinopyrazolo[1,5- a]pyrimidin-7-yl)(tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₁H₃₀BrN₅ O₄ + H]⁺ 496.1; 496.8 475 mg (96%); light yellow solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol), morpholine (0.26 mL, 3 mmol). ¹H NMR (400MHz, CDCl₃) δ ppm 7.86 (s, 1H), 6.22 (s, 1H), 3.91-3.97 (m, 2H), 3.85(t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.6 Hz, 4H), 6.64 (d, J = 6.8 Hz, 2H),3.32 (t, J = 11.4 Hz, 2H), 1.87-1.75 (m, 1H), 1.70-1.62 (m, 2H), 1.58(s, 9H), 1.29 (dd, J = 12.4, 4.8 Hz, 2H). tert-butyl(3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.9 122 mg (53%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (200 mg, 0.45 mmol), tetrahydro-2H-pyran-4-amine (55 mg, 0.54mmol), DIPEA (0.10 mL, 0.57 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s,1H), 5.93 (s, 1H), 4.97 (d, J = 7.0 Hz, 1H), 4.15 (br, s, 1H), 4.04-3.97(m, 2H), 3.93 (dd, J = 11.4, 2.6 Hz, 2H), 3.67-3.51 (m, 4H), 3.31 (td, J= 11.7, 1.8 Hz, 2H), 2.12-2.05 (m, 2H), 1.86-1.71 (m, 2H), 1.88-1.68 (m,2H), 1.57-1.45 (m, 2H), 1.37 (s, 9H). tert-butyl (3-bromo-5-(cyclohexylamino)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₃ + H]⁺ 508.2; 508.9 433 mg (85%); yellow solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol), cyclopentamine (0.34 mL, 3 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.80 (s, 1 H), 5.92 (s, 1H), 4.96-4.85 (m, 1H),3.94 (dd, J = 11.4, 2.4 Hz, 2H), 3.63 (d, J = 7.3 Hz, 2H), 3.38-3.25 (m,2H), 2.15-2.04 (m, 2H), 1.87-1.74 (m, 3H), 1.74- 1.60 (m, 4H), 1.54-1.40(m, 2H), 1.39-1.34 (m, 9H), 1.34-1.23 (m, 5H). tert-butyl(3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(isobutyl)carbamate

[C₂₀H₃₀BrN₅ O₃ + H]⁺ 468.2; 468.8 103 mg (58%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (150mg, 0.37 mmol), 4-aminotetrahydropyran (45 mg, 0.44 mmol), DIPEA (84 μL,0.48 mmol) ¹H NMR (400 MHz, CDCl₃) 7.82 (s, 1H), 5.94 (s, 1H), 4.81-4.70(m, 1H), 4.24-4.13 (m, 1H), 4.06- 3.97 (m, 2H), 3.66-3.51 (m, 4H),2.16-2.07 (m, 2H), 1.90-1.78 (m, 1H), 1.59-1.52 (m, 1H), 1.38 (s, 9 H),0.92 (d, J = 6.8 Hz, 6H). (R)-tert-butyl (3-bromo-5-((1- hydroxybutan-2-yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₁H₃₂BrN₅ O₄ + H]⁺ 498.2; 498.8 115 mg (51.8%); Colorless thick oilSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (200 mg, 0.45 mmol), R(−)-2-aminobutan-1-ol (85 mmL, 0.90mmol), DIPEA (156 mmL, 0.90 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79(s, 1H), 6.00 (s, 1H), 5.22 (d, J = 6.8 Hz, 1H), 4.08-4.02 (m, 1H),3.95-3.84 (m, 4H), 3.71-3.67 (m, 1H), 3.62 (d, J = 7.2 Hz, 2H), 3.31 (t,J = 11.6 Hz, 2H), 1.83- 1.56 (m, 4H), 1.37 (s, 9H), 1.31-1.20 (m, 3H),1.03 (t, J = 7.4 Hz, 3H). tert-butyl (3-bromo-5-(((2S,3S)-2-hydroxypentan-3- yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₂H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.9 145 mg (31.5%); White foam Startingmaterials: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (400 mg, 0.90 mmol),(2S,3S)-3-aminopentan-2-ol hydrochloride (250 mg, 1.79 mmol), DIPEA (625mmL, 3.59 mmol), 1,4-Dioxane (10 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79(s, 1H), 6.00 (s, 1H), 5.27 (br, s, 1H), 3.98-3.92 (m, 4H), 3.62 (d, J =7.2 Hz, 2H), 3.35-3.29 (m, 2H), 2.96 (s, 1 H),1.84-1.72 (m, 2H),1.70-1.61 (m, 3H), 1.37 (s, 9H), 1.30-1.25 (m, 4H), 1.00 (t, J = 7.2 Hz,3H). tert-butyl (3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5- a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₅H₃₈BrN₅ O₆ + H]⁺ 584.2; 584.9 159 mg (70%); clear oil; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (200 mg, 0.39 mmol), 4-aminotetrahydropyran (79mg, 0.78 mmol), DIPEA (137 μL, 0.78 mmol).(1r,4r)-4-(((3-bromo-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(4- methoxybenzyl)amino)methyl) cyclohexanol

[C₂₆H₃₄BrN₅ O₃ + H]⁺ 544.2; 544.2 179 mg (73%); white solid; free baseSMs:(1r,4r)-4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)methyl)cyclohexanol (215 mg, 0.45 mmol), tetrahydro-2H-pyran-4-amine (0.453 g,4.5 mmol) in dioxane (4 mL) at 170° C. for 8 h. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.82 (s, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H),5.17 (s, 1H), 4.83 (s, 2H), 4.05-3.89 (m, 3H), 3.79 (s, 3H), 3.63-3.46(m, 3H), 3.42 (d, J = 6.3 Hz, 2 H), 2.06-1.87 (m., 4H), 1.80-1.60 (m,3H), 1.57-1.39 (m, 2H), 1.30-1.11 (m, 2H), 1.01-0.88 (m, 2H).tert-butyl(3-bromo-5-(((2S,3S)-2- hydroxypentan-3-yl)amino)pyrazolo[1,5-a]pyrimidin- 7-l)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.3 9.55 g (84%); off white solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (10.0 g, 22 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride(4.7 g, 33 mmol), DIPEA (15.6 mL, 89 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm.80 (s, 1H), 5.99 (s, 1H), 5.14 (br.s, 1H), 4.00-3.93 (m, 4H), 3.62 (d,J = 7.2 Hz, 2H), 3.33 (td, J = 12 Hz, 2.0 Hz, 2H), 2.69 (br. s, 1H),1.84-1.73 (m, 2H), 1.71-1.63 (m, 3H), 1.37 (s, 9H), 1.34-1.27 (m, 5H),1.01 (t, J = 7.2 Hz, 3H). (S)-tert-butyl(3-bromo-5-((1-hydroxy-3-methylbutan-2- yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4- yl)methyl)carbamate

[C₂₂H₃₄BrN₅ O₄ + H]⁺ 512.2; 512.2 6.02 g (88%); off white solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (6.0 g, 13.4 mmol), (S)-2-amino-3-methylbutan-1-ol (2.08 g,20.2 mmol), DIPEA (7.02 mL, 40.3 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm7.78 (s, 1H), 6.05 (s, 1H), 5.38 (d, J = 6.4 Hz, 1H), 3.93-3.90 (m, 2H),3.85-3.83 (m, 2H), 3.74-3.69 (m, 1H), 3.61 (d, J = 7.6 Hz, 2H), 3.30 (t,J = 11.6 Hz, 2H), 2.02- 1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.65-1.58 (m,2H), 1.37 (s, 9H), 1.31-1.27 (m, 1 H), 0.99 (t, J = 6.4 Hz, 6H).tert-butyl (3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl) ((tetrahydro- 2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 524.2; 524.1 8.0 g (97%); cream solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.0 g, 15.0 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride(3.58 g, 23.0 mmol), DIPEA (10.95 mL, 62.0 mmol) ¹H NMR (400 MHz, CDCl₃)δ ppm 7.77 (s, 1H), 6.00 (s, 1H), 5.49 (br. s, 1H), 4.16 (br. s, 1H),4.07- 4.04 (m, 1H), 3.92 (dd, J = 11.6 Hz, 2.8 Hz, 2H), 3.60 (d, J = 7.2Hz, 2H), 3.31 (td, J = 11.6 Hz, 2.0 Hz, 2H), 1.82-1.77 (br. m, 3H),1.72-1.58 (br. m, 6H), 1.49-1.41 (br. m, 2H), 1.36 (s, 9H), 1.30-1.23(m, 2 H). (S)-tert-butyl(3-bromo-5-((2- hydroxy-2,4-dimethylpentan-3-yl)amino)pyrazolo[1,5-a]pyrimidin- 7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₄H₃₈BrN₅ O₄ + H]⁺ 540.2; 540.2 5.50 g (60%); off white solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.5 g, 16.8 mmol), (S)-3-amino-2,4-dimethylpentan-2-olhydrochloride (4.24 g, 25.2 mmol), DIPEA (11.7 mL, 67.2 mmol) ¹H NMR(400 MHz, CDCl₃) δ ppm 7.80 (s, 1H), 6.04 (s, 1H), 3.97-3.93 (m, 2H),3.63 (d, J = 7.2 Hz, 2H), 3.36-3.30 (m, 2H), 2.31-2.24 (m, 1H),1.85-1.79 (m, 1H), 1.76-1.58 (m, 3H), 1.37-1.34 (m, 14H), 1.33-1.27 (m,5H) , 0.99 (d, J = 6.8 Hz, 6H). (S)-tert-butyl(3-bromo-5-((1-cyclopropyl-2-hydroxy-2- methylpropyl)amino)pyrazolo [1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₄H₃₆BrN₅ O₄ + H]⁺ 538.2; 538.3 7.50 g (83%); cream solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.0 g, 15.0 mmol),(S)-1-amino-1-cyclopropyl-2-methylpropan-2-ol hydrochloride (4.89 g,25.0 mmol), DIPEA (11.7 mL, 67.3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm7.79 (s, 1H), 6.01 (s, 1H), 5.25 (d, J = 7.2 Hz, 1H), 3.95 (dd, J = 11.6Hz, 2.4 Hz, 2H), 3.61 (d, J = 7.2 Hz, 2H), 3.39-3.30 (m, 3H), 1.86-1.73(m, 1H), 1.69-1.62 (m, 2H), 1.38 (s, 14 H), 1.34-1.25 (m, 4H), 1.06-0.99(m, 1H), 0.79-0.74 (m, 1H), 0.56-0.50 (m, 2H), 0.41-0.39 (m, 1H).tert-butyl(3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)(cyclopropylmethyl)carbamate

[C₂₁H₃₀BrN₅ O₃ + H]⁺ 480.2; 480.3 8.5 g (79%); beige solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(cyclopropylmethyl)carbamate(9.0 g, 22.5 mmol), (1R,2S)-2-aminocyclohexanol.HCl (4.08 g, 27.0 mmol),DIPEA (3.47 g, 25.1 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (s, 1H),6.08 (s, 1H), 5.33-5.19 (m, 1H), 4.26-4.14 (m, 1H), 4.13-4.06 (m, 1H),3.61 (d, J = 7.3 Hz, 2H), 2.51 (br. s, 1H), 1.89-1.62 (m, 8H), 1.55-1.45(m, 2H), 1.40 (s, 9H), 1.06-0.95 (m, 1H), 0.47-0.38 (m, 2H), 0.17-0.07(m, 2H). tert-butyl (3-bromo-5- (cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert- butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate

[C₂₇H₄₀BrN₅ O₅ + H]⁺ 594.2; 594.3 0.40 g (67%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.45 g, 0.83mmol), cyclopentylamine (0.085 g, 1.0 mmol), DIPEA (0.21 g, 1.66 mmol).¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 5.94 (s, 1H), 5.08 (br. s,1H), 4.23 (br. s, 1H), 3.85- 3.72 (m, 2H), 2.28-2.06 (m, 5H), 2.02-1.89(m, 2H), 1.81-1.61 (m, 5H), 1.48 (s, 4H), 1.44 (s, 9H), 1.36 (s, 9H).tert-butyl (3-bromo-5-((1- (hydroxymethyl)cyclopentyl)amino)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₄BrN₅ O₄ + H]⁺ 524.2; 524.3 10.6 g (75%); yellow solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (12.0 g, 26.9mmol), (1- aminocyclopentyl)methanol (4.64 g, 40 mmol), DIPEA (9.6 mL,54 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.75 (s, 1H), 6.36 (br. s, 1H),6.06 (s, 1H), 5.96 (s, 1H), 3.89 (dd, J = 11.3, 2.8 Hz, 2H), 3.67 (d, J= 4.0 Hz, 2H), 3.59 (d, J = 7.3 Hz, 2H), 3.27 (t, J = 11.5 Hz, 2H), 1.94(d, J = 7.8 Hz, 2H), 1.83-1.53 (m, 8H), 1.39 (s, 9H), 1.33-1.17 (m, 3H).tert-butyl (3-bromo-5-(((1S,2R)-2- hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(((R)- tetrahydrofuran-3- yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.3 9.14 g (90%); white solid; free baseSMs: (R)-tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydrofuran-3-yl)methyl)carbamate (2.155 g, 5 mmol), (1R,2S)-2-aminocyclohexanolhydrochloride (1.137 g, 7.5 mmol), DIPEA (3.3 mL, 20 mmol), NMP (12 mL),in each vial, 4 vials in total. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (s,1H), 5.99 (s, 1H), 5.31 (br. s., 1H), 4.26-4.15 (m, 1H), 4.10 (br. s.,1H), 3.90-3.66 (m, 6H), 3.50 (dd, J = 8.8, 5.5 Hz, 1H), 2.56-2.45 (m,1H), 1.97 (dd, J = 12.5, 5.3 Hz, 1H), 1.89-1.56 (m, 7H), 1.51 (d, J =4.3 Hz, 2H), 1.41-1.35 (m, 9H). tert-butyl (3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-7-yl)(((S)-tetrahydrofuran-3- yl)methyl)carbamate

[C₂₂H₃₂BrN₅ O₄ + H]⁺ 510.2; 510.2 453 mg (89%); white solid; free baseSMs: (S)-tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydrofuran-3-yl)methyl)carbamate (431mg, 1 mmol), (1R,2S)-2-aminocyclohexanolhydrochloride (303 mg, 2 mmol), DIPEA (0.66 mL, 4 mmol) ¹H NMR identicalto (R)-isomer

Synthesis of tert-butyl(3-bromo-5-(cyclopentyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol) andcyclopentan-ol (129 mg, 1.5 mmol, 1.5 equiv) in DMF (8 mL) at 0° C. wasadded 60% NaH (160 mg, 4 mmol, 4 equiv). The resulting mixture wasstirred at rt for 1 h. After cooling to 0° C., quenching with satd NH₄Cland H₂O, it was extracted with EtOAc and purified by flashchromatography (gradient: EtOAc/hex 0-35%) to give the title compound(224 mg, 45%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92 (s,1H), 6.19 (s, 1H), 5.59-5.68 (m, 1H), 3.94 (dd, J=11.3, 3.3 Hz, 2H),3.64 (d, J=7.3 Hz, 2H), 3.37-3.26 (m, 2H), 2.15-2.01 (m, 2H), 1.92-1.75(m, 5H), 1.73-1.59 (m, 4H), 1.36 (s, 9H), 1.30 (dd, J=12.7, 4.1 Hz, 2H).

The following intermediates were synthesized according to General MethodD:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform tert-butyl (3-bromo-5-((tetrahydro- 2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H- pyran-4-yl)methyl)carbamate

[C₂₂H₃₁BrN₄ O₅ + H]⁺ 511.2; 511.9 158 mg (69%); clear oil; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (200 mg, 0.45 mmol), tetrahydro-2H-pyran-4-ol (84 mg, 0.82mmol), 60% NaH (72 mg, 1.8 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94 (s,1 H), 6.24 (s, 1H), 5.51-5.42 (m, 1H), 4.07-3.88 (m, 4H), 3.66 (d, J =7.3 Hz, 2H), 3.46-3.25 (m, 4H), 3.08-2.96 (m, 1H), 2.22-2.12 (m, 2H),1.92-1.79 (m, 2H), 1.64 (t, J = 13.6 Hz, 4H), 1.37 (s, 9H).3-bromo-5-chloro-7-((tetrahydro- 2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine

[C₁₂H₁₃BrCl N₃O₂ + H]⁺ 347.99; 348.0 770 mg (100%); white solid; freebase SMs: 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (585 mg, 2.2mmol), (tetrahydro-2H-pyran-4- yl)methanol (280 mg, 2.4 mmol), 60% NaH(263 mg, 6.6 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1H), 6.25 (s,1H), 4.23 (d, J = 7.0 Hz, 2H), 4.06 (dd, J = 11.2, 4.1 Hz, 2H), 3.48(td, J = 12.0, 2.0 Hz, 2H), 2.47-2.28 (m, 1H), 1.87 (d, J = 11.8 Hz,2H), 1.55-1.45 (m, 2H). tert-butyl (3-bromo-5-(cyclohexyloxy)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₃H₃₃BrN₄ O₄ + H]⁺ 509.2; 509.9 281 mg (62%); white solid; free baseSMs tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (400 mg, 0.89 mmol), cyclohexanol (134 mg, 1.34 mmol), 60% NaH(72 mg, 2 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 6.21 (s, 1H), 5.23-5.33 (m, 1H), 3.94 (d, J = 11.0 Hz, 2H), 3.65 (d, J = 7.0 Hz,2H), 3.39-3.26 (m, 2 H), 2.06 (br, s, 2H), 1.82 (dd, J = 7.3, 3.8 Hz, 3H), 1.70-1.44 (m, 8H), 1.42-1.23 (m, 11H).

Synthesis of tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-21-pyran-4-yl)methyl)carbamate

Using Phenol:

To a solution of tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate(2.01 g, 4.51 mmol) and phenol (1.27 g, 13.53 mmol, 3 equiv) in DMF (15mL) was added K₂CO₃ (1.84 g, 13.53 mmol, 3 equiv). The resulting mixturewas stirred O/N at rt and quenched with H₂O (150 mL). After extractingwith EtOAc (60 mL×2), it was concentrated to dryness and purified byflash chromatography twice (gradient: EtOAc/DCM 0-50%; EtOAc/hex 30-80%)to give the desired product (2.09 g, 92%) as white foam. ¹H NMR (400MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.49-7.44 (m, 2H), 7.33-7.28 (m, 3H),6.44 (s, 1H), 3.98-3.92 (m, 2H), 3.70 (d, J=7.2 Hz, 2H), 3.33 (t, J=11.8Hz, 2H), 1.90-1.78 (m, 1H), 1.70-1.62 (m, 2H), 1.37 (s, 9H), 1.32 (dd,J=12.8, 4.8 Hz, 2H).

Using Phenoxide:

To a solution of tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate(4.55 g, not very dry, assuming 10 mmol) in DMF (20 mL) in was addedPhONa (1.22 g, 10.5 mmol). The resulting mixture was stirred at rt for30 min and quenched with H₂O (200 mL). The precipitates were collectedby suction filtration and dried to give the desired product (3.88 g) aswhite solid.

The following intermediates were synthesized according to General MethodE:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate

[C₂₀H₂₃BrN₄ O₄ + H]⁺ 463.1; 463.6 3.20 g (quantitative); white solid;free base SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate(2.71 g, 6.69 mmol), PhOH (1.23 g, 13.4 mmol). ¹H NMR (400 MHz, CDCl₃) δppm 7.97 (s, 1H), 7.49-7.43 (m, 2H), 7.32-7.27 (m, 3H), 6.61 (s, 1H),3.94 (t, J = 5.0 Hz, 2H), 3.59 (t, J = 5.0 Hz, 2H), 3.22 (s, 3H), 1.38(s, 9H). tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-methoxyethyl)carbamate

[C₁₉H₂₂BrN₅ O₄ + H]⁺ 464.1; 464.7 261 mg (56%); light brown oil; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate(406 mg, 1 mmol), 3-hydroxypyridine (190 mg, 2 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.61 (d, J = 2.8 Hz, 1H), 8.49 (dd, J = 4.8, 1.2 Hz, 1H),7.94 (s, 1H), 7.74-7.69 (m, 1H), 7.37 (dd, J = 8.4, 4.8 Hz, 1H), 6.68(s, 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.0 Hz, 2H), 3.22 (s,3H), 1.35 (s, 9H). tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₂H₂₆BrN₅ O₄ + H]⁺ 504.1; 504.8 485 mg (96%); light brown foam; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol), 3-hydroxypyridine (190 mg, 2 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.63 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 4.8, 1.2Hz, 1H), 7.95 (s, 1H), 7.76-7.72 (m, 1H), 7.39 (dd, J = 8.6, 4.8 Hz,1H), 6.51 (s, 1H), 3.98-3.88 (m, 2H), 3.70 (d, J = 7.2 Hz, 2H), 3.30 (t,J = 7.2 Hz, 2H), 1.88-1.76 (m, 1H), 1.68-1.61 (m, 2H), 1.40-1.25 (m,11H; s, 9H at 1.34 and m, 2H). tert-butyl (3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

[C₂₃H₂₆BrFN₄ O₄ + H]⁺ 521.1; 521.8 487 mg (94%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (446 mg, 1 mmol), 3-fluorophenol (224 mg, 2 mmol). ¹H NMR (400MHz, CDCl₃) δ ppm 7.99 (s, 1H), 7.45-7.39 (m, 1H), 7.15-7.09 (m, 2H),7.06-6.99 (m, 1H), 6.46 (s, 1H), 3.98-3.82 (m, 2H), 3.71 (d, J = 6.8 Hz,2H), 3.33 (t, J = 7.2 Hz, 2H), 1.90-1.78 (m, 1H), 1.70-1.63 (m, 2H) 1.38(s, 9H), 1 32 (dd, J = 12.6, 3.8 Hz, 2H). tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-morpholinoethyl)carbamate

[C₂₃H₂₈BrN₅ O₄ + H]⁺ 518.1; 518.8 3.60 g (99%); white foam; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(3.22 g, 7.0 mmol), PhONa (893 mg, 0.77 mmol). ¹H NMR (400 MHz, CDCl₃) δppm 7.96 (s, 1H), 7.50-7.44 (m, 2H), 7.32-7.26 (m, 3H), 6.52 (s, 1H),3.94 (t, J = 6.0 Hz, 2H), 3.40-3.33 (m, 4H), 2.56 (t, J = 6.0 Hz, 2H),2.33-2.27 (m, 4H), 1.38 (s, 9H). 3-bromo-5-phenoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy) pyrazolo[1,5-a]pyrimidine

[C₁₈H₁₈BrN₃ O₃ + H]⁺ 404.1; 404.6 241 mg (83%); white solid; free baseSMs:3-bromo-5-chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine(250 mg, 0.72 mmol), sodium phenoxide (92mg, 0.79 mmol) ¹H NMR (400 MHz,CDCl₃) δ ppm 7.98 (s, 1 H), 7.49-7.40 (m, 2H), 7.31-7.27 (m, 3H), 5.88(s, 1H), 4.17 (d, J = 6.5 Hz, 2H), 4.06 (dd, J = 11.5, 3.3 Hz, 2H), 3.48(t, J = 11.3 Hz, 2 H), 2.45-2.29 (m, 1H), 1.87 (d, J = 11.3 Hz, 2H),1.54-1.45 (m, 2H). tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(3-morpholinopropyl)carbamate

[C₂₄H₃₀BrN₅ O₄ + H]⁺ 534.2; 534.1 374 mg (quantitative); white solid;free base SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(3-morpholinopropyl)carbamate(200 mg, 0.42 mmol), PhONa (53 mg, 0.46 mmol). ¹H NMR (400 MHz, CDCl₃) δppm 7.97 (s, 1H), 7.51-7.42 (m, 2H), 7 35-7.21 (m, 3H), 6.47 (s, 1H),3.86 (t, J = 7.3 Hz, 2H), 3.63 (t, J = 4.5 Hz, 4H), 2.41-226 (m, 6H),1.88-1.74 (m, 2H), 1.38 (s, 9H). tert-butyl (3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7- yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

[C₂₄H₂₉BrN₄ O₄ + H]⁺ 517.1; 517.9 192 mg (85%); white solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (200 mg, 0.44 mmol), PhONa (56 mg, 0.48 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.51-7.43 (m, 2H), 7.33-7.28 (m,3H), 6.43 (s, 1H), 3.94 (dd, J = 11.7, 3.9 Hz, 2H), 3.87-3.80 (m, 2H),3.35 (t, J = 11.2 Hz, 2H), 1.62-1.49 (m, 5H), 1.39 (s, 9H), 1.35-1.25(m, 2H). tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

[C₂₃H₂₈BrN₅ O₄ + H]⁺ 518.1; 518.8 190 mg (84%); off-white solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (200 mg, 0.44 mmol), pyridin-3-ol (124 mg, 1.31mmol), K₂CO₃ (241 mg, 1.747 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.66(d, J = 2.5 Hz, 1H), 8.56 (dd, J = 4.8, 1.3 Hz, 1H), 7.99 (s, 1H), 7.77(ddd, J = 8.2, 2.7, 1.4 Hz, 1H), 7.43 (dd, J = 8.3, 4.8 Hz, 1H), 6.52(s, 1H), 3.94 (dd, J = 11.0, 3.8 Hz, 2H), 3.89-3.80 (m, 2H), 3.35 (t, J= 11.0 Hz, 2H), 1.68-1.49 (m, 5H), 1.44-1.37 (m, 9H), 1.37-1.21 (m, 2H).tert-butyl (3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2- methylpropyl)carbamate

[C₂₆H₃₃BrN₄ O₆ + H]⁺ 577.2; 577.9 115 mg (54%); light brown solid; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (190 mg, 0.37 mmol), NaOPh (51 mg, 0.44 mmol). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 7.47-7.40 (m, 2H), 7.33-7.24(m, 3H), 6.51 (s, 1H), 4.07 (s, 2H), 1.57 (s, 6H), 1.34 (s, 9H) 1.25 (s,9H). tert-butyl (3-bromo-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate

[C₂₀H₂₄BrN₅ O₃ + H]⁺ 462.1; 462.8 132 mg (77%); light brown oil; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (150mg, 0.37 mmol), 3-hydroxypyridine (176 mg, 1.85 mmol), DBU (281 mg, 1.85mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65 (s, 1H), 8.57-8.51 (m, 1H),7.99 (s, 1H), 7.79-7.72 (m, 1H), 7.45-7.39 (m, 1H), 6.53 (s, 1H), 3.65(d, J = 7.3 Hz, 2H), 1.93-1.82 (m, 1H), 1.43-1.30 (m, 9H), 0.95 (d, J =6.8 Hz, 6H). tert-butyl (3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate

[C₂₅H₃₂BrN₅ O₆ + H]⁺ 578.2; 578.9 120 mg (53%); light brown oil; freebase SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (200 mg, 0.39 mmol), 3-hydroxypyridine (183 mg,1.93 mmol), DBU (293 mg, 1.93 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.65(s, 1 H), 8.56-8.50 (m, 1H), 7.97 (s, 1H), 7.79-7.71 (m, 1H), 7.44-7.37(m, 1H), 6.59 (s, 1H), 4.07 (s, 2H), 1.58 (s, 6H), 1.34 (s, 9H), 1.21(s, 9H). (1r,4r)-4-(((3-bromo-5- phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(4- methoxybenzyl)amino)methyl) cyclohexanol

[C₂₇H₂₉BrN₄ O₃ + H]⁺ 537.1/539.1. 537.1/539.1 0.18 g (89%); clear film;free base SMS:(1r,4r)-4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)methyl)-cyclohexanol (180 mg, 0.37 mmol) and PhONa (108 mg, 0.93 mmol), 50° C.,70 min. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.93 (s, 1H), 7.40 (t, J = 8.30Hz, 2H), 7.24-7.17 (m, 3H), 7.10 (d, J = 8.30 Hz, 2H), 6.84 (d, J = 8.8Hz, 2H), 5.56 (s, 1H), 4.96 (s, 2H), 3.80 (s, 3H), 3.55-3.475 (m, 1H),3.48 (d, J = 6.8 Hz, 2H), 2.00-1.88 (m, 2H), 1.80-1.60 (m, 3H),1.26-1.10 (m, 2H), 1.05-0.84 (m, 2H) tert-buty1(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7- yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate

[C₂₇H₃₄BrN₅ O₆ + H]⁺ 604.2; 604.3 0.23 g (46%); yellow solid; free baseSMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.45 g, 0.83mmol), 3-hydroxypyridine (0.39 g, 4.14 mmol), DBU (0.63 g, 4.14 mmol) ¹HNMR (400 MHz, CDCl₃) δ ppm 8.65 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 4.6,1.4 Hz, 1H), 7.98 (s, 1H), 7.78-7.73 (m, 1H), 7.46-7.40 (m, 1H), 6.50(s, 1H), 3.89 (d, J = 6.8 Hz, 2H), 2.30-2.15 (m, 3H), 2.02-1.93 (m, 2H),1.50 (s, 3H), 1.45 (s, 9H), 1.38 (s, 9H). tert-butyl4-(((3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-4- fluoropiperidine-1-carboxylate

[C₂₈H₃₄BrF₂ N₅O₅ + H]⁺ 638.2; 638.2 7.8 g (97%); pale yellow solid; freebase SMs: tert-butyl4-(((3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylate (7.04 g,12.6 mmol), 3- fluorophenol (2.0 g, 17.6 mmol), K₂CO₃ (3.47 g, 25.1mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.98 (s, 1H), 7.46-7.37 (m, 1H),7.16-7.07 (m, 2H), 7.05-6.95 (m, 1H), 6.55 (s, 1H), 4.14-3.85 (m, 4H),3.11-2.92 (m, 2H), 2.02-1.86 (m, 2H), 1.81-1.62 (m, 2H), 1.47 (s, 9H),1.35 (s, 9H). tert-butyl (3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2- morpholinoethyl)carbamate

[C₂₃H₂₇BrFN₅ O₄ + H]⁺ 536.1; 536.2 5.42 g (quant.); light brown foam;free base SMs: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(4.61 g, 10 mmol), 3-fluorophenol (2.24 g, 20 mmol), K₂CO₃ (2.76 g, 20mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94 (s, 1H), 7.42-7.35 (m, 1H),7.10-7.02 (m, 2H), 7.00-6.95 (m, 1H), 6.54 (s, 1H), 3.92 (t, J = 5.8 Hz,2H), 3.35-3.28 (m, 4H), 2.55 (t, J = 5.8 Hz, 2H), 2.27 (t, J = 4.2 Hz,4H), 1.36 (s, 9H). tert-butyl (3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5- a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate

[C₂₃H₂₆BrF₂ N₅O₄ + H]⁺ 554.1; 554.1 532 mg (100%); white solid; freebase SMS: tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(mg, 1 mmol), 2,3-difluorophenol (390 mg, 3 mmol), K₂CO₃ (552 mg, 4mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1 H), 7.18-7.18 (m, 3 H),6.64 (s, 1 H), 3.97 (t, J = 5.6 Hz, 2 H), 3.32 (br. s., 4 H), 2.58 (t, J= 5.8 Hz, 2 H), 2.29 (t, J = 4.4 Hz, 4 H), 1.39 (s, 9 H). tert-butyl(3-bromo-5-(3- fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)((1-methylpiperidin- 4-yl)methyl)carbamate

[C₂₄H₂₉BrFN₅ O₃ + H]⁺ 533.1 534.1 0.338 g (60%); light grey solid; freebase Sms: (General Method E)_ tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((1-methylpiperidin-4-yl)methyl)carbamate (0.483 g, 1.05 mmol),3-fluorophenol (0.413 g, 3.7 mmol), K₂CO₃ (0.44 g, 3.2 mmol) ¹H NMR (400MHz, CD₃OD) δ ppm 8.05 (s, 1H), 7.55-7.39 (m, 1H), 7.20-7.13 (m, 2H),7.07 (dd, J = 2.5, 0.8 Hz, 1H), 6.83 (s, 1H), 3.72 (d, J = 7.3 Hz, 2H),2.84 (d, J = 11.8 Hz, 2H), 2.23 (s, 3H), 2.00-1.88 (m., 2H), 1.85-1.76(m, 2H), 1.65-1.50 (m, 1H), 1.35 (s, 9H), 1.33-1.22 (m, 2H) tert-butyl(3-bromo-5-(2,3- difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-(4-fluoropiperidin- 1-yl)ethyl)carbamate

[C₂₄H₂₇BrF₃ N₅O₃ + H]⁺ 570.1 570.3 0.289 g (68%); pale foam; free baseSms: (General Method E)_tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(2-(4-fluoropiperidin-1-yl)ethyl)carbamate (0.354 g, 0.74 mmol),2,3-difluorophenol (0.288 g, 2.2 mmol), K₂CO₃ (0.31 g, 2.2 mmol) ¹H NMR(400 MHz, CDCl₃) δ ppm 7.97 (s, 1H), 7.21-7.07 (m, 3H), 6.66 (s, 1H),4.65-4.43 (m, 1H), 3.95 (t, J = 5.8 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H),2.48-2.36 (m, 2H), 2.31-2.20 (m, 2H), 1.45-1.34 (m, 4H), 1.39 (s, 9H)

The following intermediates were synthesized according to General MethodF (Suzuki):

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform 2-chloro-N-cyclopropyl-4-(4-((4- methoxybenzyl)((tetrahydro-2H-pyran-4- yl)methyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₃ClN₆ O₃S + H]⁺ 593.2; 593.7 1.3 g (68%); yellow solid; free baseSMs:8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-atetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.6 g, 3.3 mmol),(3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (0.87 g, 3.6mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 1 H), 8.19 (d, J = 1.5 Hz,1 H), 7.94 (dd, J = 8.0, 2.0 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.23(d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 6.50 (br. s., 1 H),5.32 (br. s, 2 H), 3.97 (d, J = 11.0 Hz, 2 H), 3.81 (s, 3 H), 3.29-3.41(m, 2 H), 2.92-3.00 (m, 1 H), 2.62 (s, 3 H), 2.09-2.19 (m, 1 H),1.58-1.66 (m, 4 H), 1.36-1.49 (m, 2 H), 0.87-0.95 (m, 2 H), 0.64-0.72(m, 2 H). N-cyclopropyl-4-(4-((4- methoxybenzyl)(2-morpholinoethyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₅IN₇O₃ S + H]⁺ 574.3; 574.5 1.3 g (68%); yellow solid; free baseSMS:8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-(2-morpholinoethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.10 g, 2.28 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide(982 mg, 3.42 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 8.03 (d, J= 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.85(d, J = 8.4 Hz, 2H), 5.38-5.22 (m, 2H), 4.15-4.00 (m, 2H), 3.78 (s, 3H),3.68-3.57 (m, 4H), 2.96-2.86 (m, 1H), 2.64 (t, J = 6.6 Hz, 2H), 2.56 (s,3H), 2.52-2.38 (m, 4H), 0.90- 0.80 (m, 2H), 0.66-0.60 (m, 2H).N-cyclopropyl-4-(4-((4- methoxybenzyl)(3- morpholinoethyl)amino)-2-(methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₁H₃₇N₇O₃ S + H]⁺ 588.3; 588.2 1.3 g (68%); pale solid; free base SMs:8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-(3-morpholinopropyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.6 g, 3.156 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide(1.359 g, 4.734 mmol). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1 H), 8.10 (d,J = 8.5 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H),6.88 (d, J = 8.8 Hz, 2 H), 6.25 (br. s., 1 H), 5.15-5.52 (br. s., 2 H),3.88-4.11 (br. s., 2 H), 3.81 (s, 3 H), 3.70 (t, J = 4.6 Hz, 4 H),2.89-2.99 (m, 1 H), 2.61 (s, 3 H), 2.32-2.47 (m, 6 H), 1.87-1.97(m, 2H), 0.86-0.94 (m, 2 H), 0.61-0.68 (m, 2 H). N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran- 4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₃₀H₃₄N₆O₃ S + H]⁺ 559.2; 559.5 815 mg (70%); white solid; free baseSMs:8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 g, 2.09 mmol),N-cyclopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(900 mg, 3.14 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (s, 1 H), 8.09(d, J = 8.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2 H), 6.26 (br. s., 1 H), 5.36 (br. s., 1 H),3.97 (dd, J = 11.2, 3.1 Hz, 3 H), 3.80 (s, 3 H), 3.35 (t, J = 11.2 Hz, 1H), 2.93 (s, 1 H), 2.61 (s, 3 H), 2.06-2.20 (m, 1 H), 1.54-1.66 (m, 2H), 1.35-1.48 (m, 2 H), 0.83-0.93 (m, 2 H), 0.61-0.68 (m, 2 H).N-cyclopropyl-4-(4-((((cis)-4- hydroxycyclohexyl)methyl)(4-methoxybenzyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₂H₃₈N₆O₃ S + H]⁺ 587.3; 587.2 0.347 g (74%); a cream colored solid;free base SMs:(cis)-4-(((8-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)(4-methoxybenzyl)amino)methyl)cyclohexanol (0.39 g, 0.80 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.37 g, 1.2mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (s, 1 H), 7.69-7.81 (m, 2 H),7.27 (d, J = 8.00 Hz, 1 H), 7.13 (d, J = 7.28 Hz, 2 H), 6.77 (d, J =8.53 Hz, 2 H), 5.05-5.50 (br. s., 2 H), 3.85 (br. s., 1 H), 3.70 (s, 3H), 3.55-4.05 (br.s. 2H), 2.73-2.84 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3H), 1.87 (br. s., 1 H), 1.64 (br. s., 2 H), 1.33-1.49 (m, 6 H),0.71-0.80 (m, 2 H), 0.53 (br. s., 2 H). N-cyclopropyl-4-(4-((4-methoxybenzyl)(2- morpholinoethyl)amino)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₁H₃₇N₇O₃ S + H]⁺ 588.3; 588.2 0.34 g (94%); light yellow solid; freebase SMs: 8-bromo-N-(4-methoxybenzyl)-2-(methylthio)-N-(2-morpholinoethyl) pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.30 g, 0.61 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.26 g, 0.85 mmol). ¹H NMR (400 MHz, CD₃OD)δ ppm 8.36-8.43 (m, 1 H), 7.98-8.03 (m, 1 H), 7.94 (d, J = 7.50 Hz, 1H), 7.36 (d, J = 8.00 Hz, 1 H), 7.33 (d, J = 8.50 Hz, 2 H), 6.91 (d, J =8.50 Hz, 2 H), 5.31-5.37 (br.s., 2 H), 4.13-4.20 (m, 2 H), 3.79 (s, 3H), 3.54-3.60 (m, 4 H), 2.82-2.92 (m, 1 H), 2.64-2.73 (m, 2 H), 2.60 (s,3 H), 2.47-2.53 (m, 4 H), 2.46 (s, 3 H), 0.78-0.86 (m, 2 H), 0.58-0.67(m, 2 H).

Synthesis ofN-cyclopropyl-2-methyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method FutilizingN-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyraz-olo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide(410 mg, 0.72 mmol) in DCM/TFA (2:1, 6 mL) at 60° C. for 30 h. The crudeproduct was purified by flash chromatography (SiO₂, 20-100% EtOAc/DCM)to give the desired product as a yellow solid (320 mg, 100%). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.22 (s, 1H), 7.83-7.90 (m, 2H), 7.40 (d, J=8.0Hz, 1H), 6.56 (t, J=6.6 Hz, 1H), 5.90 (br s, 1H), 4.02 (dd, J=11.4, 3.6Hz, 2H), 3.59 (t, J=6.9 Hz, 2H), 3.42 (t, J=11.7 Hz, 2H), 2.91-2.94 (m,1H), 2.64 (s, 3H), 2.53 (s, 3H), 1.96-1.99 (m, 1H), 1.73 (d, J=11.8 Hz,2H), 1.41-1.49 (m, 2H), 0.87-0.92 (m, 2H), 0.62-0.65 (m, 2H); MS ESI[M+H]⁺ 453.5, calcd for [C₂₃H₂₈N₆O₂S+H]⁺ 453.20.

The following intermediates were synthesized according to General MethodF (deprotection):

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform 2-chloro-N-cyclopropyl-4-(2- (methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₅ClN₆O₂S + H]⁺ 473.1; 473.7 1.1 g (100%); brown solid; free baseSMs:2-chloro-N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.3 g, 2.3mmol). N-cyclopropyl-4-(2-(methylthio)-4- ((3-morpholinopropyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₃H₂₉N₇O₂S + H]⁺ 468.3; 468.2 724 mg (79%); yellow solid; free baseSMs: N-cyclopropyl-4-(4-((4-methoxybenzyl)(3-morpholinopropyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.15 g, 1.96mmol). ¹H NMR (400 MHz, CDCl₃) δ 9.11 (br. s., 1 H), 8.27 (s, 1 H), 8.09(d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 6.25 (br. s., 1 H),3.93 (t, J = 4.4 Hz, 4 H), 3.79 (d, J = 5.5 Hz, 2 H), 2.90-2.97 (m, 1H), 2.62- 2.68 (m, 5 H), 2.57 (br. s., 4 H), 1.88 (br. s., 2 H),0.86-0.94 (m, 2 H), 0.61-0.67 (m, 2 H).N-cyclopropyl-4-(2-(methylthio)-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₆N₆O₂S + H]⁺ 439.2; 439.6 561 mg (90%); beige solid; free baseSMs:N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (800 mg, 1.43mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1 H), 8.07 (d, J = 8.5 Hz,2 H), 7.80 (d, J = 8.5 Hz, 2 H), 6.54-6.62 (m, 1 H), 6.27 (br. s., 1 H),4.02 (dd, J = 11.0, 3.8 Hz, 2 H), 3.59 (t, J = 6.8 Hz, 2 H), 3.42 (t, J= 12.0 Hz, 2 H), 2.89-2.98 (m, 1 H), 2.64 (s, 3 H), 1.91-2.05 (m, 1 H),1.68-1.77 (m, 2 H), 1.37- 1.52 (m, 2 H), 0.85-0.93 (m, 2 H), 0.61-0.68(m, 2 H).

The following intermediates were synthesized according to General MethodK:

MS calculated; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺Salt form N-cyclopropyl-4-(4-((4- methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2- (methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₁H₃₆N₆O₅S + H]⁺ 605.25; 605.4 140 mg (89%); yellow solid; free baseSMs:N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (150mg, 0.26 mmol), mCPBA (180 mg, 0.79 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm8.38 (s, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H),7.42 (d, J = 8.0 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 5.91 (br. s., 1H), 4.97-5.19 (m, 2 H), 4.31-4.53 (m, 2 H), 3.99 (d, J = 8.3 Hz, 2 H),3.81 (s, 3 H), 3.26-3.45 (m, 5 H), 2.85-3.02 (m, 1 H), 2.53 (s, 3 H),1.46-1.71 (m, 5 H),0.82-0.99 (m, 2 H), 0.59-0.69 (m, 2 H).2-chloro-N-cyclopropyl-4-(2- (methylsulfonyl)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₅ClN₆O₄S + H]⁺ 505.1; 505.6 1.2 g (100%); yellow solid; free baseSMs:2-chloro-N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (1.0 g, 2.1 mmol),mCPBA (1.4g. 6.3 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.39 (s, 1 H),7.95 (s, 1 H), 7.85 (dd, J = 8.1, 1.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 6.3 Hz, 1 H), 6.51 (br s, 1 H), 4.05 (dd, J = 11.0, 3.2Hz, 2 H), 3.74 (t, J = 6.6 Hz, 2 H), 3.38-3.47 (m, 5 H), 2.94-3.00 (m, 1H), 2.02-2.08 (m, 1 H), 1.75 (d, J = 11.7 Hz, 2 H), 1.44-1.53 (m, 2 H),0.87-0.96 (m, 2 H), 0.66-0.72 (m, 2 H).N-cyclopropyl-4-(2-(methylsulfonyl)- 4-((3-morpholinopropyl)amino)pyrazolo [1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₃H₂₉N₇O₄S + H]⁺ 500.2; 500.1 126 mg (16%); pale solid; free base SMs:N-cyclopropyl-4-(2-(methylthio)-4-((3-morpholinopropyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (724 mg, 1.55 mmol), mCPBA (1042 mg, 4.65 mmol). 1H NMR(400 MHz, CDCl3) δ 12.28-12.38 (m, 1 H), 8.29 (s, 1 H), 7.91 (d, J = 8.3Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 6.52-6.60 (m, 1 H), 4.53-4.59 (m, 2H), 3.93 (br. s., 2 H), 3.82 (d, J = 12.0 Hz, 2 H), 3.68 (br. s., 2 H),3.34 (br. s., 4 H), 2.92-3.04 (m, 4 H), 2.36 (br. s., 2 H), 0.87-0.92(m, 2 H), 0.71 (br. s., 2 H). N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₂H₂₆N₆O₄S + H]⁺ 471.2; 471.5 412 mg (69%); white solid; free baseSMs:N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (535 mg, 1.27 mmol), mCPBA (849 mg, 3.8mmol) N-cyclopropyl-4-(4-((((cis)-4- hydroxycyclohexyl)methyl)(4-methoxybenzyl)amino)-2- (methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2- methylbenzamide

[C₃₂H₃₈N₆O₅S + H]⁺ 619.3; 619.2 0.279 g (76%); white powder; free baseSMs:N-cyclopropyl-4-(4-((((cis)-4-hydroxycyclohexyl)methyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide (0.347g, 0.59 mmol), mCPBA (0.397 g, 1.8 mmol). 1H NMR (400 MHz, CDCl3) δ ppm8.37 (s, 1 H), 7.83 (d, J = 7.03 Hz, 1 H), 7.77 (s, 1 H), 7.25-7.46(br.m. 1 H), 7.42 (d, J = 8.03 Hz, 2 H), 6.88 (d, J = 8.28 Hz, 2 H),5.87-4.98 (m, 2 H), 5.03-5.14 (br.s., 1H), 4.34-4.49 (m, 1 H), 3.96-4.13(m, 2 H), 3.80 (s, 3 H), 3.35 (br. S., 3 H), 2.87-2.98 (m, 1 H), 2.53(s, 3 H), 1.79 (br. S., 2 H), 1.56 (br.s, 9 H), 0.84-0.96 (m, 2 H),0.54-0.71 (m, 2 H).

Synthesis ofN-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5-a][3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method Ffollowed by General Method K. A solution ofN-cyclopropyl-4-(4-((4-methoxybenzyl)(2-morpholinoethyl)amino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benz-amide(701 mg, 1.22 mmol) in TFA/DCM (5 ml/10 ml) was heated in microwave for2 h at 80° C. After removal of solvent, it was redissolved DCM (20 ml)and treated with mMCPBA (3 eq). After stirring for 3 h at rt, additionalmCPBA (2 eq) was added and it was stirred for 2 h. Solvents were removedand the crude product was purified by flash chromatography (SiO₂, 10-80%EtOAc/DCM then 10-90% MeOH/DCM) to give the desired product as a yellowsolid (345 mg, TFA salt, 47%). NMR ¹H NMR (400 MHz, CDCl₃) δ ppm 9.79(brs, 1H), 9.01 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H),9.26 (d, J=8.4 Hz, 2H), 4.13-3.00 (m, 15H), 2.90-2.82 (m, 1H), 0.75-0.68(m, 2H), 0.62-0.56 (m, 2H); MS ESI [M+H]⁺ 486.4, calcd for[C₂₂H₂₇N₇O₄S+H]⁺ 486.2.

Synthesis ofN-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method EutilizingN-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide(87 mg, 0.14 mmol), phenol (68 mg, 0.72 mmol), and DBU (0.11 mL, 0.72mmol) in DME (2 mL) at 100° C. to rt for 1 h. The crude product waspurified by flash chromatography (SiO₂, 10-80% EtOAc/DCM) to give thedesired product as a white solid (70 mg, 79%). ¹H NMR (400 MHz, CDCl₃) δppm 8.22 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.37-7.46 (m,2H), 7.30 (d, J=8.0 Hz, 1H), 7.22-7.28 (m, 3H), 7.16 (d, J=8.5 Hz, 2H),6.86 (d, J=8.3 Hz, 2H), 5.91 (br. s., 1H), 5.66 (d, J=15.8 Hz, 2H), 4.07(t, J=6.7 Hz, 1H), 3.93 (d, J=9.3 Hz, 2H), 3.80 (s, 3H), 3.29 (t, J11.2Hz, 2H), 2.90 (td, J=7.0, 3.4 Hz, 1H), 2.42 (s, 3H), 1.96-2.10 (m, 2H),1.33-1.65 (m, 4H), 0.82-0.91 (m, 2H), 0.55-0.65 (m, 2H); MS ESI [M+H]⁺619.5, calcd for [C₃₆H₃₈N₆O₄+H]⁺ 619.30.

Synthesis ofN-cyclopropyl-4-(2-(dimethylamino)-4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method CutilizingN-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide(50 mg, 0.083 mmol) and 2,2,2-trifluoro-1,1-N dimethyl-ethylaminehydrochloride (20 mg, 0.12 mmol) and DIPEA (0.020 mL, 0.12 mmol) in DMF(2 mL) at 100° C. for 18 h. The crude product was purified by RPchromatography (C18 column, 10-90% MeCN/H₂O) to give the desired productas a pale yellow solid (23 mg, 58%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21(s, 1H), 7.96 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H),7.24 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.34 (br. s., 2H), 3.90(dd, J=11.2, 3.4 Hz, 4H), 3.76 (s, 3H), 3.21 (s, 6H), 2.84-2.87 (m, 1H),2.44 (s, 3H), 2.07-2.30 (m, 1H), 1.59 (d, 0.1=12.5 Hz, 2H), 1.19-1.43(m, 4H), 0.75-0.87 (m, 2H), 0.55-0.69 (m, 2H); MS ESI [M+H]⁺ 570.5,calcd for [C₃₂H₃₉N₇O₃+H]⁺570.31.

Synthesis ofN-cyclopropyl-2-methyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method KutilizingN-cyclopropyl-2-methyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide(360 mg, 0.80 mmol) and mCPBA (540 mg, 2.39 mmol) in DCM (12 mL) at 0°C. to rt for 2 h. The crude product was purified by flash chromatography(SiO₂, 40-100% EtOAc/DCM) to give the desired product as a pale yellowsolid (185 mg, 48%). MS ESI [M+H]⁺ 485.4, calcd for [C₂₃H₂₈N₆O₄S+H]⁺485.19.

Synthesis of tert-butyl(3-(4-(cycloproplcarbamoyl)-3-methylphenyl)-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

According to General method H, a mixture of sodium benzenesulfinate(1.968 g, 12 mmol, 1.2 equiv) and tert-butyl(3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate(4.455 g, 10 mmol) in DMF (40 mL) was heated at 60° C. for 2 h. Afterremoval of solvents, it was purified by flash chromatography (gradient:EtOAc/hex 0-80%) to give tert-butyl(3-bromo-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (5.37 g, 97%) as yellow solid. ¹H NMR (400 MHz, CDCl₃)δ ppm 8.23 (s, 1H), 8.19-8.15 (m, 2H), 7.73-7.69 (m, 1H), 7.65-7.60 (m,2H), 7.55 (s, 1H), 3.95-3.89 (m, 2H), 3.79 (d, J=7.6 Hz, 2H), 3.33-3.25(m, 2H), 1.82-1.72 (m, 2H), 1.64-1.57 (m, 2H), 1.36 (s, 9H), 1.30-1.24(m, 2H). MS ESI [M+H]⁺ 551.1, calcd for [C₂₃H₂₇BrN₄O₅S+H]⁺ 551.1.

According to General method I, to a mixture of the above compound (5.37g, 9.75 mmol) andN-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(4.11 g, 13.65 mmol, 1.4 equiv) in THF (60 mL) was added 2 M K₃PO₄ (14.6mL, 29.2 mmol, 3 equiv), followed by PdCl₂dppfDCM (318 mg, 0.39 mmol, 4mol %). The resulting mixture was purged with Ar and then heated at 60°C. for 1.5 h. It was diluted with brine (30 mL), extracted with EtOAcand combined. After removal of solvents, the residue was purified byflash chromatography (gradient: EtOAc/hex 0-80%) to give the titlecompound (6.02 g) as yellow foam. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.54 (s,1H), 8.20-8.17 (m, 2H), 7.77-7.72 (m, 2H), 7.70-7.62 (m, 3H), 7.56 (s,1H), 7.36 (d, J=8.0 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 3.96-3.91 (m, 2H),3.83 (d, J=7.2 Hz, 2H), 3.31 (td, J=11.6, 1.8 Hz, 2H), 2.97-2.91 (m,1H), 2.50 (s, 3H), 1.87-1.67 (m, 1H), 1.68-1.63 (m, 2H), 1.38 (s, 9H),1.34-1.27 (m, 2H), 0.96-0.89 (m, 2H), 0.68-0.63 (m, 2H). MS ESI [M+H]⁺646.2, calcd for [C₃₄H₃₉N₅O₆S+H]⁺ 646.3.

Preparation of Exemplary Compounds of the Invention Example A1.N-Cyclopropyl-4-(2-(dimethylamino)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide

The title compound was synthesized according to General Method FutilizingN-cyclopropyl-4-(2-(dimethylamino)-4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide(23 mg, 0.040 mmol) in DCM:TFA (1 mL:3 mL) at 100° C. for 30 min.Purification by prep-HPLC, followed by trituration with MeOH gave thetitle compound as a free base (white solid, 8.1 mg, 45%). ¹H NMR (400MHz, CDCl₃) δ ppm 8.11 (s, 1H), 7.77-7.93 (m, 2H), 7.37 (d, J=8.5 Hz,1H), 6.39 (t, J=6.1 Hz, 1H), 5.90 (br. s., 1H), 4.02 (dd, J=11.8, 3.5Hz, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.41 (t, J=11.5 Hz, 2H), 3.27 (s, 6H),2.82-2.97 (m, 1H), 2.52 (s, 3H), 1.87-2.06 (m, 1H), 1.73 (d, J=12.8 Hz,2H), 1.39-1.49 (m, 2H), 0.81-0.96 (m, 2H), 0.56-0.66 (m, 2H); MS ESI[M+H]⁺ 450.5, calcd for [C₂₄H₃₁N₇O₂+H]⁺ 450.25.

Example A2.4-(2-(Cyclopentylamino)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N-cyclopropyl-2-methylbenzamide

The title compound was synthesized according to General Method CutilizingN-cyclopropyl-2-methyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide(88 mg, 0.18 mmol) and cyclopentylamine (0.040 mL, 0.40 mmol) in THF (5mL) at 35° C. for 6 h. The crude product was purified by RPchromatography (C18 column, 20-90% MeCN/H₂O) to give the desired productas a white solid (68 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (s,1H), 7.66-7.96 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 6.45 (br. s., 1H), 5.98(br. s., 1H), 5.89-6.33 (m, 1H), 5.09 (br. s., 1H), 4.26-4.42 (m, 1H),4.00 (dd, J=11.2, 3.4 Hz, 2H), 3.45 (br. s., 2H), 3.39 (td, J=11.7, 1.9Hz, 2H), 2.86-2.93 (m, 1H), 2.50 (s, 3H), 2.12 (br. s., 2H), 1.83-1.99(m, 2H), 1.69-1.81 (m, 5H), 1.56 (d, J=5.8 Hz, 2H), 1.33-1.47 (m, 2H),0.78-0.94 (m, 2H), 0.56-0.65 (m, 2H); MS ESI [M+H]⁺490.5, calcd for[C₂₇H₃₅N₇O₂+H]⁺ 490.29.

Example A4.2-Chloro-N-cyclopropyl-4-(2-phenoxy-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

The title compound was synthesized according to General Method Eutilizing2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide(100 mg, 0.20 mmol), phenol (75 mg, 0.79 mmol), and DBU (0.12 mL, 0.79mol) in DME (4 mL) at 100° C. for 1 h. The crude product was purified byflash chromatography (C18 column, 20-90% MeCN/H₂O) followed bytrituration with MeOH to give the desired product as a white solid (34mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (br. s., 1H), 7.89 (br. s.,1H), 7.69 (br. s., 2H), 7.41-7.54 (m, 2H), 7.28-7.37 (m, 3H), 6.74 (br.s., 1H), 6.46 (br. s., 1H), 4.03 (d, J=8.0 Hz, 2H), 3.58 (br. s., 2H),3.41 (t, J10.2 Hz, 2H), 2.84-3.03 (m, 1H), 1.91-2.11 (m, 1H), 1.71 (d,J=11.8 Hz, 2H), 1.34-1.51 (m, 2H), 0.89 (d, J=6.5 Hz, 2H), 0.57-0.73 (m,2H); MS ESI [M+H]⁺ 519.6, calcd for [C₂₇H₂₇ClN₆O₃+H]⁺ 519.18.

Example A5.2-chloro-4-(2-(cyclopentyloxy)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N-cyclopropylbenzamide

The title compound was synthesized according to General Method Dutilizing2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide(100 mg, 0.20 mmol), NaH (100 mg, 60% in mineral oil, 2.5 mmol), andcyclopentanol (0.040 mL, 0.44 mol) in DMF (4 mL) at 0° C. to rt for 1 h.The crude product was purified by RP chromatography (C18 column, 20-90%MeCN/H₂O) followed by trituration with MeOH to give the desired productas a white solid (48 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20 (s,1H), 8.11 (s, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 6.58(br. s., 1H), 6.48 (br. s., 1H), 5.39-5.62 (m, 1H), 4.02 (d, J=8.0 Hz,2H), 3.59 (t, J=6.4 Hz, 2H), 3.42 (t, J=10.8 Hz, 2H), 2.96 (d, J=3.5 Hz,1H), 2.06-2.19 (m, 2H), 1.93-2.05 (m, 3H), 1.81-1.92 (m, 2H), 1.63-1.78(m, 4H), 1.38-1.51 (m, 2H), 0.84-0.97 (m, 2H), 0.61-0.74 (m, 2H); MS ESI[M+H]⁺ 511.7, calcd for [C₂₆H₃₁ClN₆O₃+H]⁺ 511.21.

Example C1.N-cyclopropyl-4-(4-((3-morpholinopropyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

4-(3-((8-(4-(cyclopropylcarbamoyl)phenyl)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)propyl)-4-hydroxymorpholin-4-ium2,2,2-trifluoroacetate (42 mg, 0.065 mmol) was converted into freedissolved in CDCl3 before the solution of (pinB)2 (17 mg, 0.065 mmol) inDCM was added dropwise at rt. The resulting reaction mixture was stirredat rt for 5 min followed by removal of solvent. The residue was purifiedby HPLC to give the title compound (30 mg, 70% yield) as light yellowsolid. 1H NMR (400 MHz, CD3OD) δ ppm 8.39 (s, 1H), 7.85 (d, J=8.5 Hz,2H), 7.69 (d, J=8.3 Hz, 2H), 7.42-7.54 (m, 2H), 7.24-7.36 (m, 3H), 4.07(d, J=12.3 Hz, 2H), 3.81 (t, J=12.3 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H),3.54 (d, J=12.3 Hz, 2H), 3.21-3.29 (m, 2H), 3.14 (t, J=10.9 Hz, 2H),2.79-2.90 (m, 1H), 2.08-2.22 (m, 2H), 0.76-0.85 (m, 2H), 0.59-0.68 (m,2H); MS ESI [M+H]⁺ 514.3, calcd for [C₂₈H₃₁N₇O₃+H]⁺ 514.3.

The following exemplary compounds were synthesized according to GeneralMethods C, D, E or F, as indicated:

MS calculated Yield; MS ESI Appearance; Example/IUPAC name Structure[M + H]⁺ Salt form A3: N-cyclopropyl-2-methyl-4-(2-phenoxy-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2 499.5 131 mg (46%); white solid; free base SMs(method F):N-cyclopropyl-4-(4-((4-methoxybenzyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-methylbenzamide(354 mg, 0.57 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1 H), 7.64(s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.39-7.45 (m, 2 H), 7.25-7.31 (m, 3H), 7.21 (d, J = 8.0 Hz, 1 H), 6.87 (t, J = 6.1 Hz, 1 H), 6.11 (br. s.,1 H), 3.96 (dd, J = 11.4, 3.4 Hz, 2 H), 3.50 (t, J = 6.7 Hz, 2 H), 3.35(td, J = 11.7, 1.6 Hz, 2 H), 2.87-2.92 (m, 1 H), 2.32 (s, 3 H),1.87-2.01 (m, 1 H), 1.61-1.70 (m, 2 H), 1.38-1.45 (m, 2 H), 0.79-0.86(m, 2 H), 0.55-0.61 (m, 2 H). A10: N-cyclopropyl-4-(2-phenoxy-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₇H₂₈N₆O₃ + H]⁺ 485.2 485.5 46 mg (45%); white solid; free base SMs(method E): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.21 mmol), phenol (79 mg, 0.84 mmol), DBU (0.13 mL, 0.84 mmol). ¹H NMR(400 MHz, CDCl₃) δ 18.26 (s, 1 H), 7.86 (d, J = 9.3 Hz, 2 H), 7.67 (d, J= 8.5 Hz, 2 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.26-7.33 (m, 3 H), 6.84 (br.s., 1 H), 6.24 (br. s., 1 H), 4.01 (dd, J = 11.3, 3.3 Hz, 2 H),3.51-3.58 (m, 2 H), 3.40 (td, J = 11.8, 2.0 Hz, 2 H), 2.86-2.95 (m, 1H), 1.92-2.06 (m, 1 H), 1.63-1.75 (m, 2 H), 1.31-1.49 (m, 2 H),0.82-0.92 (m, 2 H), 0.56-0.69 (m, 2 H). A11: 4-(2-(cyclopentyloxy)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N- cyclopropylbenzamide

[C₂₆H₃₂N₆O₃ + H]⁺ 477.25 477.5 39 mg (39%); white solid; free base SMs(method D): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.21 mmol), NaH (44 mg, 60% in mineral oil, 1.11 mmol), andcyclopentanol (0.049 g, 0.57 mol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s,1 H), 8.04 (d, J = 8.5 Hz, 2 H), 7.79 (d, J = 8.5 Hz, 2 H), 6.53-6.60(m, 1 H), 6.24 (br. s., 1 H), 5.47-5.55 (m, 1 H), 4.01 (dd, J = 11.0,4.0 Hz, 2 H), 3.59 (t, J = 6.4 Hz, 2 H), 3.35-3.46 (m, 2 H), 2.88-2.97(m, 1 H), 2.04-2.14 (m, 2 H), 1.92-2.02 (m, 3 H), 1.81-1.90 (m, 2 H),1.69-1.77 (m, 2 H), 1.62-1.69 (m, 2 H), 1.37-1.51 (m, 2 H), 0.85-0.92(m, 2 H), 0.60-0.67 (m, 2 H). A13: N-cyclopropyl-4-(2-(pyridin-3-yloxy)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)-pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₂₇N₇O₃ + H]⁺ 486.2 486.4 18 mg (18%); white solid; free base SMs(method E): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.21 mmol), 3- hydroxypyridine (79 mg, 0.84 mmol), DBU (0.13 mL, 0.84mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.68 (s, 1 H), 8.56 (d, J = 4.8 Hz,1 H), 8.28 (d, J = 1.3 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 2 H), 7.63-7.73(m, 3 H), 7.42 (dd, J = 8.3, 4.8 Hz, 1 H), 6.78 (br. s., 1 H), 6.23 (br.s., 1 H), 3.97-4.06 (m, 2 H), 3.57 (d, J = 6.5 Hz, 2 H), 3.41 (t, J =11.4 Hz, 2 H), 2.85-2.97 (m, 1 H), 1.92-2.06 (m, 1 H), 1.71 (d, J = 12.0Hz, 2 H), 1.35-1.51 (m, 2 H), 0.83-0.92 (m, 2 H), 0.58- 0.68 (m, 2 H).A6: 2-chloro-N-cyclopropyl-4-(2- morpholino- 4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₅H₃₀ClN₇O₃ + H]⁺ 512.2 512.7 46 mg (46%); beige solid; free base SMs(method C):2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.20 mmol), morpholine (0.46 mmol) ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11(s, 1 H), 8.03 (s, 1 H), 7.87 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 7.3 Hz,1 H), 6.53 (s, 1 H), 6.43 (s, 1 H), 3.98-4.08 (m, 2 H), 3.82-3.98 (m, 4H), 3.75-3.87 (m, 4 H), 3.48-3.59 (m, 2 H), 3.42 (t, J = 10.0 Hz, 2 H),2.92-3.04 (m, 1 H), 1.93-1.98 (m, 1 H), 1.58-1.77 (m, 2 H), 1.36-1.52(m, 2 H), 0.75-0.95 (m, 2 H), 0.61-0.73 (m, 2 H). A9:N-cyclopropyl-4-(2-(4- hydroxypiperidin-1-yl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5- a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₃₄N₈O₃ + H]⁺ 507.3 507.5 25.3 mg (31%); white solid; free base SMs(method C):N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol),piperidin-4-ol hydrochloride (55 mg, 0.4 mmol), DIPEA (0.14 ml, 0.8mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (s, 1H), 8.02 (d, J = 8.4 Hz,2H), 7.77 (d, J = 8.4 Hz, 2H), 6.85-6.78 (m, 1H), 6.32 (s, 1H),4.54-4.43 (m, 2H), 4.03-3.94 (m, 1H), 3.8-3.65 (m, 6H), 3.48-3.38 (m,2H), 2.97-2.88 (m, 1H), 2.68 (t, J = 6.0 Hz, 2H), 2.60-2.48 (m, 4H),2.05-1.94 (m, 2H), 1.65- 1.53 (m, 2H), 0.93-0.83 (m, 2H), 0.66-0.57 (m,2H). A7: N-cyclopropyl-4-(4-((2- morpholinoethyl)amino)-2-phenoxypyrazolo[1,5-a][1,3,5]triazin- 8-yl)benzamide

[C₂₄H₂₉N₇O₃ + H]⁺ 500.2 500.5 25.4 mg (32%); yellow solid; free base SMs(method E):N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol), phenol (38mg, 0.4 mmol), DBU (0.06 ml, 0.4 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm8.26 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H),7.47-7.41 (m, 2H), 7.32-7.23 (m, 4H), 6.29 (s, 1H), 3.80-3.68 (m, 6H),2.94-2.87 (m, 1H), 2.69 (t, J = 6.0 Hz, 2H), 2.57-2.49 (m, 4H),0.90-0.83 (m, 2H), 0.55-0.49 (m, 2H). A8: N-cyclopropyl-4-(4-((2-morpholinoethyl)amino)-2-(pyridin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin- 8-yl)benzamide

[C₂₆H₂₈N₈O₃ + H]⁺ 501.2 501.3 22.5 mg (28%); white solid; free base SMs(method E):N-cyclopropyl-4-(2-(methylsulfonyl)-4-((2-morpholinoethyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide TFA salt (97 mg, 0.16 mmol),3-hydroxypyridine (38 mg, 0.2 mmol), DBU (0.06 ml, 0.4 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.67 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.2Hz, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.70-7.65 (m, 3H), 7.41(dd, J = 8.2, 4.6 Hz, 1H), 7.37-7.33 (m, 1H), 6.33 (s, 1H), 3.80-3.69(m, 6H), 2.95-2.87 (m, 1H), 2.71 (t, J = 6.0 Hz, 2H), 2.58-2.51 (m, 4H),0.90- 0.84 (m, 2H), 0.66-0.61 (m, 2H). A12: N-cyclopropyl-4-(2-(methylsulfonyl)-4-((3- morpholinopropyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₈H₃₁N₇O₄ + H]⁺ 530.2 530.3 62 mg (48%); off white solid; TFA saltSMs: (methodE)N-cyclopropyl-4-(2-(methylsulfonyl)-4-((3-morpholinopropyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg, 0.2 mmol), phenol (75 mg 0.820mmol), DBU (122 mg, 0.802 mmol), small amount of peroxide carried overfrom previous step (sulfide → sulfone oxidation). ¹H NMR (400 MHz,CD₃OD) δ 8.35 (s, 1 H), 7.82 (d, J = 8.5 Hz, 2 H), 7.66 (d, J = 8.5 Hz,2 H), 7.43- 7.52 (m, 2 H), 7.25-7.35 (m, 3 H), 4.06-4.18 (m, 2 H),3.93-4.02 (m, 2 H), 3.63-3.85 (m, 8 H), 2.83 (tt, J = 7.4, 3.8 Hz, 1 H),2.26-2.37 (m, 2 H), 0.77-0.85 (m, 2 H), 0.62-0.68 (m, 2 H). A14:2-chloro-N-cyclopropyl-4-(4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-((tetrahydro-2H- pyran-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide

[C₂₆H₃₁ClN₆O₄ + H]⁺ 527.2 527.7 69 mg (69%); white solid; free base SMs(method D):2-chloro-N-cyclopropyl-4-(2-(methylsulfonyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.20 mmol), NaH (100 mg, 60% in mineral oil, 2.5 mmol), andtetrahydro-2H-pyran-4-ol (0.044 g, 0.44 mol) ¹H NMR (400 MHz, CDCl₃) δ8.21 (s, 1 H), 8.14 (s, 1 H), 7.79 (s, 2 H), 6.63 (t, J = 6.1 Hz, 1 H),6.50 (br. s., 1 H), 5.27-5.33 (m, 1 H), 4.09 (dt, J = 11.6, 3.9 Hz, 2H), 4.02 (dd, J = 11, 3.9 Hz, 2 H), 3.59- 3.67 (m, 4 H), 3.42 (t, J =10.3 Hz, 2 H), 2.93-2.99 (m, 1 H), 2.21-2.25 (m, 2 H), 1.91-2.02 (m, 3H), 1.74 (d, J = 11.8 Hz, 2 H), 1.40-1.50 (m, 2 H), 0.91 (q, J = 7.1 Hz2 H), 0.68 (q, J = 8.0 Hz, 2 H). A15: 4-(2-(cyclopentylamino)-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)-N- cyclopropylbenzamide

[C₂₆H₃₃N₇O₂ + H]⁺ 476.3 476.5 45 mg (45%); white solid; free base SMs(method C): N-cyclopropyl-4-(2-(methylthio)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamide (100 mg,0.21 mmol), cyclopentylamine (0.046 g, 0.47 mol). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.12 (s, 1 H), 8.05 (br. s., 2 H), 7.77 (d, J = 8.3 Hz, 2H), 6.41 (br. s., 1 H), 6.28 (br. s., 1 H), 5.11 (br. s., 1 H),4.30-4.42 (m, 1 H), 4.01 (dd, J = 11.5, 3.0 Hz, 2 H), 3.29-3.56 (m, 4H), 2.87-2.96 (m, 1 H), 2.02-2.22 (m, 2 H), 1.87-2.00 (m, 1 H),1.62-1.83 (m, 6 H), 1.49-1.61 (m, 2 H), 1.35-1.48 (m, 2 H), 0.84-0.91(m, 2 H), 0.58-0.67 (m, 2 H).

The following exemplary compounds were synthesized according to GeneralMethods C, D, E or F, as indicated:

Example number MS calcd; MS ESI [M + H]⁺; Structure HPLC purity ¹H NMR

C2 [C₂₇H₃₀N₆O₃ + H]⁺ 487.2; 487.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.26 (s, 1 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H),7.45 (t, J = 8.0 Hz, 2 H), 7.25-7.35 (m, 3 H), 5.92 (d, J = 7.5 Hz, 1H), 4.30 (dq, J = 13.7, 6.8 Hz, 1 H), 4.01 (dd, J = 11.3, 3.5 Hz, 2 H),3.54 (d, J = 7.0 Hz, 2 H), 3.39 (t, J = 11.0 Hz, 2 H), 1.90-2.04 (m, 1H), 1.69 (d, J = 12.0 Hz, 2 H), 1.33-1.48 (m, 2 H), 1.27 (d, J = 6.5 Hz,6 H).

C3 [C₂₇H₃₀N₆O₃ + H]⁺ 487.2; 487.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.29 (s, 1 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H),7.51 (t, J = 8.0 Hz, 2 H), 7.31-7.41 (m, 3 H), 6.78 (br. s, 1 H), 4.09(m, J = 7.3 Hz, 2 H), 3.61 (d, J = 6.8 Hz, 2 H), 3.47 (t, J = 11.4 Hz, 2H), 2.53-2.64 (m, 1 H), 2.05 (br. s., 1 H), 1.77 (d, J = 12.8 Hz, 2 H),1.41- 1.55 (m, 2 H), 1.34 (d, J = 6.8 Hz, 6 H).

C4 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.22 (s, 1 H), 8.03 (d, J = 8.3 Hz, 2 H), 7.79 (d, J = 8.3 Hz, 2 H),6.61-6.68 (m, 1 H), 6.05 (d, J = 7.5 Hz, 1 H), 5.47-5.55 (m, 1 H), 5.11(br. s, 1 H), 4.24-4.38 (m, 1 H), 4.01 (dd, J = 11.4, 3.4 Hz, 2 H), 3.57(t, J = 6.5 Hz, 2 H), 3.40 (t, J = 10.9 Hz, 2 H), 2.04-2.14 (m, 2 H),1.92-2.01 (m, 2 H), 1.78-1.90 (m, 2 H), 1.60-1.76 (m, 4 H), 1.36-1.49(m, 2 H), 1.22-1.32 (m, 6 H).

C5 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm9.17 (br. s, 1 H), 8.16 (s, 1 H), 7.83 (d, J = 8.3 Hz, 2 H), 7.56 (d, J= 8.5 Hz, 2 H), 7.50 (s, 1 H), 6.93-7.04 (m, 1 H), 5.45-5.58 (m, 1 H),4.05 (dd, J = 11.5, 3.5 Hz, 2 H), 3.59 (t, J = 6.5 Hz, 2 H), 3.44 (t, J= 11.3 Hz, 2 H), 2.52-2.65 (m, 1 H), 1.58-2.12 (m, 10 H), 1.38-1.53 (m,2 H), 1.22-1.32 (m, 6 H).

C6 [C₂₄H₂₄N₆O₃ + H]⁺ 445.2; 445.4; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.25 (s, 1 H), 7.82 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 8.0 Hz, 2 H),7.39-7.51 (m, 2 H), 7.25-7.36 (m, 3 H), 7.06 (br. s., 1 H), 6.23 (br.s., 1 H), 3.85 (q, J = 5.4 Hz, 2 H), 3.66 (t, J = 4.8 Hz, 2 H), 3.44 (s,3 H), 2.81-2.99 (m, 1 H), 0.78-0.98 (m, 2 H), 0.53-0.72 (m, 2 H).

C7 [C₂₇H₂₇FN₆O₃ + H]+ 503.2; 503.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.22 (s, 1 H), 8.03 (t, J = 8.4 Hz, 1 H), 7.54-7.68 (m, 2 H), 7.46 (t, J= 7.8 Hz, 2 H), 7.23-7.35 (m, 3 H), 6.82 (d, J = 12.5 Hz, 1 H), 4.00 (d,J = 8.3 Hz, 2 H), 3.55 (d, J = 6.5 Hz, 2 H), 3.39 (t, J = 11.5 Hz, 2 H),2.94 (br. d, J = 3.0 Hz, 1 H), 1.98 (br. s., 1 H), 1.68 (d, J = 11.5 Hz,2 H), 1.33- 1.48 (m, 2 H), 0.80-0.92 (m, 2 H), 0.57-0.67 (m, 2 H).

C8 [C₂₃H₂₈N₆O₃ + H]+ 437.2; 437.2; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.13 (s, 1 H), 7.93 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H),7.05-7.15 (m, 1 H), 6.66 (br. s., 1 H), 5.46-5.51 (m, 1 H), 3.84 (q, J =5.2 Hz, 2 H), 3.63-3.71 (m, 2 H), 3.42 (s, 3H), 2.94 (m, J = 6.9, 3.4Hz, 1 H), 2.02-2.14 (m, 2 H), 1.91-2.00 (m, 2 H), 1.79-1.90 (2 H, m),1.58-1.72 (m, 2 H), 0.83-0.95 (m, 2 H), 0.64- 0.74 (m, 2 H).

C9 [C₂₇H₂₈ClN₇O₂ + H]⁺ 445.2; 445.4; 96.4% at 254 nm (400 MHz, CDCl₃) δppm 8.27 (s, 1 H), 8.17 (s, 1 H), 7.81 (s, 2 H), 7.77 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.9 Hz, 2 H), 7.13 (t, J = 1.0 Hz, 1 H), 7.06 (s, 1 H),6.55 (br. s., 2 H), 4.04 (d, J = 7.3 Hz, 2 H), 3.55 (t, J = 6.8 Hz, 2H), 3.43 (t, J = 11.7 Hz, 2 H), 2.92- 3.00 (m, 1 H), 1.91-2.13 (m, 1 H),1.74 (d, J = 12.3 Hz, 2 H), 1.36-1.53 (m, 2 H), 0.91 (s, 2 H), 0.62-0.80 (m, 2 H).

C10 [C₂₈H₃₁N₇O₂ + H]⁺ 498.6; 498.5; 98.5% at 254 nm (400 MHz, CDCl₃) δ8.17 (s, 1 H), 8.00 (s, 1 H), 7.79 (d, J = 8.3 Hz, 2 H), 7.74 (d, J =7.5 Hz, 1 H), 7.34-7.44 (m, 3 H), 7.11 (t, J = 7.4 Hz, 1 H), 7.02 (s, 1H), 6.54 (t, J = 6.0 Hz, 1 H), 5.90 (br. s., 1 H), 4.04 (dd, J = 11.3,3.8 Hz, 2 H), 3.54 (t, J = 6.7 Hz, 2 H), 3.43 (t, J = 11.0 Hz, 2 H),2.88-2.99 (m, 1 H), 2.56 (s, 3 H), 1.93-2.10 (m, 1 H), 1.76 (d, J = 10.5Hz, 2 H), 1.38-1.53 (m, 2 H), 0.84-0.96 (m, 2 H), 0.58- 0.68 (m, 2 H).

C11 [C₂₆H₃₂FN₇O₂ + H]⁺ 494.3; 494.5; 95% at 254 nm (400 MHz, CDCl₃) δppm 14.23 (br. s., 1 H), 9.86 (br. s., 1 H), 7.91-8.32 (m, 2 H),7.30-7.79 (m, 3 H), 6.87 (br. s., 1 H), 4.38 (br. s, 1 H), 3.94-4.16 (m,2 H), 3.54-3.81 (m, 2 H), 3.30-3.54 (m, 2 H), 2.87-3.05 (m, 1 H),1.39-2.20 (m, 12 H), 0.76- 0.96 (m, 2 H), 0.55-0.73 (m, 2 H).

C12 [C₂₈H₂₉FN₆O₄ + H]⁺ 533.2; 533.5; 95% at 254 nm (400 MHz, CDCl₃) δppm 8.22 (s, 1 H), 8.03 (t, J = 8.4 Hz, 1 H), 7.56-7.70 (m, 2 H), 7.34(t, J = 8.8 Hz, 1 H), 6.79-6.93 (m, 5 H), 5.94 (br. s., 1 H), 4.00 (dd,J = 11.3, 3.3 Hz, 2 H), 3.83 (s, 3 H), 3.54 (t, J = 6.5 Hz, 2 H), 3.39(t, J = 11.3 Hz, 2 H), 2.88-2.98 (m, 1 H), 1.89-2.04 (m, 1 H), 1.68 (d,J = 11.5 Hz, 2 H), 1.33-1.48 (m, 2 H), 0.82-0.92 (m, 2 H), 0.58- 0.67(m, 2 H).

C13 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; 96.8% at 254 nm (400 MHz, CDCl₃) δppm 8.18 (s, 1 H), 7.72-7.89 (m, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.61(t, J = 6.0 Hz, 1 H), 6.00 (br. s., 1 H), 5.39-5.56 (m, 1 H), 4.01 (dd,J = 11.3, 3.5 Hz, 2 H), 3.57 (t, J = 6.5 Hz, 2 H), 3.30-3.45 (m, 2 H),2.83-2.98 (m, 1 H), 2.51 (s, 3 H), 2.03-2.18 (m, 2 H), 1.92-2.00 (m, 2H), 1.60- 1.90 (m, 6 H), 1.34-1.51 (m, 2 H), 0.81-0.93 (m, 2 H),0.54-0.68 (m, 2 H).

C14 [C₂₈H₂₈F₂N₆O₃ + H]⁺ 535.2; 535.5; 95.4% at 254 nm (400 MHz, CDCl₃) δppm 8.21 (s, 1 H), 7.63 (s, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.26 (d, J= 8.8 Hz, 1 H), 7.05-7.20 (m, 2 H), 5.96 (br. s., 1 H), 4.00 (dd, J =11.2, 3.4 Hz, 2 H), 3.53 (d, J = 7.0 Hz, 2 H), 3.39 (t, J = 11.2 Hz, 2H), 2.79-2.96 (m, 1 H), 2.36 (s, 3 H), 1.89-2.06 (m, 1 H), 1.68 (d, J =11.5 Hz, 2 H), 1.30-1.47 (m, 2 H), 0.73-0.95 (m, 2 H), 0.49- 0.68 (m, 2H).

C15 [C₂₈H₃₆FN₇O₂ + H]⁺ 522.3; 522.5; 95% at 254 nm (400 MHz, CDCl₃) δppm 10.67 (br. s., 1 H), 8.02- 8.15 (m, 2 H), 7.82-7.93 (m, 1 H), 7.71(d, J = 8.3 Hz, 1 H), 7.04 (d, J = 13.3 Hz, 1 H), 6.81 (br. s., 1 H),4.54-4.67 (m, 1 H), 4.05 (dd, J = 11.5, 3.0 Hz, 2 H), 3.52 (t, J = 6.5Hz, 2 H), 3.43 (t, J = 10.9 Hz, 2 H), 3.14 (s, 3 H), 2.92-3.01 (m, 1 H),1.96-2.08 (m, 1 H), 1.92 (d, J = 12.3 Hz, 2 H), 1.69-1.87 (m, 5 H),1.39-1.61 (m, 6 H), 1.13-1.31 (m, 1 H), 0.84- 0.95 (m, 2 H), 0.62-0.72(m, 2 H).

C16 [C₂₆H₃₂ClN₇O₂ + H]⁺ 510.2; 510.2; 97.0% at 254 nm (400 MHz, CDCl₃) δppm 8.06 (d, J = 9.0 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.78 (d, J =8.3 Hz, 1 H), 6.53 (br. s., 1 H), 6.36 (br. s., 1 H), 4.02 (d, J = 8.5Hz, 2 H), 3.88 (br. s., 4 H), 3.51 (t, J = 6.5 Hz, 2 H), 3.41 (t, J =11.7 Hz, 2 H), 2.85-3.03 (m, 1 H), 1.87- 2.04 (m, 1 H), 1.55-1.79 (m, 8H), 1.36-1.52 (m, 2 H), 0.81-0.97 (m, 2 H), 0.60-0.73 (m, 2 H).

C17 [C₂₈H₃₀N₆O₃ +H]⁺ 499.2; 499.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.20 (s, 1 H), 7.64-7.86 (m, 2 H), 7.50-7.60 (m, 1 H), 7.40-7.49 (m, 2H), 7.24-7.36 (m, 3 H), 7.17 (br. s., 1 H), 6.72-6.82 (m, 1 H), 4.02(dd, J = 11.3, 3.5 Hz, 2 H), 3.56 (t, J = 6.5 Hz, 2 H), 3.32-3.45 (m, 2H), 2.20 (s, 3 H), 1.91-2.05 (m, 1 H), 1.71 (d, J = 12.5 Hz, 2 H), 1.53(br. s., 1 H), 1.34-1.48 (m, 2 H), 1.02-1.18 (m, 2 H), 0.66-0.93 (m, 2H).

C18 [C₂₇H₃₅N₇O₂ + H]⁺ 490.3; 490.5; 95% at 254 nm (400 MHz, MeOD-d₄) δppm 8.14 (br. s., 1 H), 7.23- 7.51 (m, 3 H), 4.41 (br. s., 1 H), 3.97(d, J = 8.5 Hz, 2 H), 3.55 (d, J = 6.5 Hz, 2 H), 3.41 (t, J = 11.7 Hz, 2H), 2.31 (s, 3 H), 2.00-2.16 (m, 3 H), 1.57-1.94 (m, 9 H), 1.31-1.48 (m,2 H), 0.80-1.03 (m, 4 H).

C19 [C₃₀H₃₃N₇O₄ + H]⁺ 556.3; 556.5; 95% at 254 nm (400 MHz, CDCl₃) δ ppm8.25 (s, 1 H), 8.14 (s, 1 H), 7.61 (s, 2 H), 7.48 (d, J = 7.8 Hz, 1 H),7.33- 7.40 (m, 1 H), 7.25-7.33 (m, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 6.98(d, J = 7.8 Hz, 1 H), 6.84 (t, J = 6.1 Hz, 1 H), 6.22 (d, J = 3.0 Hz, 1H), 3.97 (dd, J = 11.4, 3.1 Hz, 2 H), 3.44-3.54 (m, 2 H), 3.37 (t, J =11.3 Hz, 2 H), 2.79-2.92 (m, 1 H), 2.31 (s, 3 H), 2.10 (s, 3 H), 1.94(s, 1 H), 1.66 (d, J = 11.5 Hz, 2 H), 1.27-1.44 (m, 2 H), 0.76-0.88 (m,2 H), 0.54-0.65 (m, 2 H).

C20 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.5; 99.1% at 254 nm (400 MHz, CDCl₃) δppm 8.21 (s, 1 H), 7.64 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.15-7.38(m, 5 H), 6.82 (t, J = 6.1 Hz, 1 H), 5.93 (br. s., 1 H), 4.00 (dd, J =11.5, 3.5 Hz, 2 H), 3.53 (t, J = 6.5 Hz, 2 H), 3.39 (t, J = 11.0 Hz, 2H), 2.80-2.97 (m, 1 H), 2.34 (s, 3 H), 1.88-2.06 (m, 1 H), 1.68 (d, J =13.1 Hz, 2 H), 1.31-1.49 (m, 2 H), 0.77-0.96 (m, 2 H), 0.49- 0.67 (m, 2H).

C21 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.5; 98.2% at 254 nm (400 MHz, CDCl₃) δppm 8.22 (s, 1 H), 7.68 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40 (td, J= 8.3, 6.5 Hz, 1 H), 7.23-7.31 (m, 1 H), 7.07-7.15 (m, 2 H), 7.01 (t, J= 8.2 Hz, 1 H), 6.81 (t, J = 6.1 Hz, 1 H), 5.94 (d, J = 2.3 Hz, 1H),4.01 (dd, J = 11.3, 3.3 Hz, 2 H), 3.55 (t, J = 6.7 Hz, 2 H), 3.40(td, J = 11.7, 1.6 Hz, 2 H), 2.83-2.94 (m, 1 H), 2.38 (s, 3 H),1.93-2.07 (m, 1 H), 1.65-1.73 (m, 2 H), 1.33-1.50 (m, 2 H), 0.80- 0.95(m, 2 H), 0.50-0.68 (m, 2 H).

C22 [C₂₈H₃₇N₇O₂ + H]⁺ 504.3; 504.6; 95% at 254 nm (400 MHz, CDCl₃) δ ppm13.88 (br. s., 1 H), 9.82 (br. s., 1 H), 7.79-8.20 (m, 1 H), 7.50 (br.s., 3 H), 5.92-6.25 (m, 1 H), 4.02 (br. s., 3 H), 3.63 (br. s., 2 H),3.30-3.52 (m, 2 H), 2.81-3.01 (m, 1 H), 2.55 (br. s., 3 H), 1.29-2.18(m, 15 H), 0.80-0.97 (m, 2 H), 0.49-0.74 (m, 2 H).

C23 [C₂₇H₃₅N₇O₃ + H]⁺ 506.3; 506.5; 97.4% at 254 nm (400 MHz, CDCl₃) δppm 10.33 (br. s., 1 H), 8.00 (br. s., 1 H), 7.31-7.47 (m, 2 H), 7.16(br. s., 1 H), 5.95 (br. s., 1 H), 4.13 (br. s., 1 H), 4.05 (d, J = 11.3Hz, 4 H), 3.29-3.70 (m, 8 H), 2.85-2.98 (m, 1 H), 2.49 (s, 3 H),1.79-2.07 (m, 4 H), 1.73 (d, J = 10.3 Hz, 2 H), 1.37-1.55 (m, 2 H),0.80-0.96 (m, 2 H), 0.53-0.68 (m, 2 H).

C24 [C₂₉H₃₁FN₆O₃ + H]⁺ 531.2; 531.2; 95% at 254 nm (400 MHz, CDCl₃) δppm 8.34 (s, 1 H), 7.77 (s, 1 H), 7.62 (dd, J = 8.03, 1.25 Hz, 1 H),7.46 (td, J = 8.34, 6.65 Hz, 1 H), 7.24 (d, J = 8.03 Hz, 1 H), 7.09-7.18(m, 2 H), 7.05 (tdd, J = 8.50, 8.50, 2.50, 0.80 Hz, 1 H), 3.90 (br. s.,1 H), 3.41 (d, J = 7.03 Hz, 2 H), 2.85 (tt, J = 7.37, 3.80 Hz, 1 H),2.33 (s, 3 H), 1.69-1.84 (m, 3 H), 1.42-1.60 (m, 6 H), 0.77- 0.84 (m, 2H), 0.59-0.65 (m, 2 H).

C25 [C₂₉H₃₁FN₆O₄ + H]⁺ 547.2; 547.5; 95% at 254 nm (400 MHz, CDCl₃) δppm 8.22 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.25-7.31(m, 2 H), 7.22 (t, J = 8.8 Hz, 1 H), 6.70-6.84 (m, 3 H), 5.87 (br. s., 1H), 4.01 (dd, J = 11.2, 3.4 Hz, 2 H), 3.84 (s, 3 H), 3.56 (t, J = 6.5Hz, 2 H), 3.34-3.45 (m, 2 H), 2.89 (s, 1 H), 2.37 (s, 3 H), 1.93-2.04(m, 1 H), 1.70 (d, J = 11.3 Hz, 2 H), 1.35-1.49 (m, 2 H), 0.83- 0.91 (m,2 H), 0.54-0.65 (m, 2 H).

C26 [C₂₈H₂₉F₂N₇O₃ + H]+ 550.2; 550.3; 98.5% at 254 nm (400 MHz, CD₃OD) δppm 8.46 (s, 1 H), 7.72 (s, 1 H), 7.54-7.63 (m, 1 H), 7.29-7.38 (m, 2H), 7.17- 7.29 (m, 2 H), 4.08-4.21 (m, 2 H), 4.05 (t, J = 5.65 Hz, 2 H),3.70-3.91 (m, 4 H), 3.55 (t, J = 5.52 Hz, 2 H), 3.15-3.30 (m, 2 H),2.78-2.88 (m, 1 H), 2.29 (s, 3 H), 0.76-0.85 (m, 2 H), 0.56-0.64 (m, 2H).

C27 [C₂₈H₃₀FN₇O₃ + H]⁺ 532.2; 532.3; 99.5% at 254 nm (400 MHz, CD₃OD) δppm 8.45 (s, 1 H), 7.80 (s, 1 H), 7.64 (dd, J = 8.00, 1.80 Hz, 1 H),7.48-7.56 (m, 1 H), 7.25 (d, J = 8.03 Hz, 1 H), 7.09-7.22 (m, 3 H),4.04-4.20 (m, 2 H), 4.01 (t, J = 5.50 Hz, 2 H), 3.67- 3.89 (m, 4 H),3.53 (t, J = 5.50 Hz, 2 H), 3.12-3.29 (m, 2 H), 3.00 (s, 1 H), 2.81-2.89(m, 1 H), 2.32 (s, 3 H), 0.77-0.85 (m, 2 H), 0.57-0.65 (m, 2 H).

Example B1. Synthesis of tert-butyl tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a solution of tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate(1.51 g, 3 mmol) andN-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzam-ide(2.71 g, 3 equiv) in THF (12 mL) was N added 2 M K₃PO₄ (3 mL, 6 mmol, 2equiv), followed by PdCl₂dppfDCM (122 mg, 0.15 mmol, 5 mol %). Theresulting mixture was purged with Ar, and then microwaved 2 h at 120° C.After repeating the reaction on the same scale, both reactions werecombined, diluted with H₂O (30 mL) and extracted with EtOAc (30 mL×2).It was concentrated and purified by purified by flash chromatography(EtOAc/hex 0-60%) to give the intermediate as light yellow foam.

The above light yellow foam was redissolved in DCM (20 mL) and treatedwith TFA (4 mL). After stirring O/N, it was concentrated to dryness andpurified by flash chromatography (gradient: EtOAc/hex 0-100%) andtriturated with MeOH to give the title compound (1.819 g, 61% over 2steps) as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1H), 7.77(s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.32-7.27 (m,3H), 7.24 (d, J=8.0 Hz, 1H), 6.39 (t, J=6.2 Hz, 1H), 5.84-5.82 (m, 1H),5.69 (s, 1H), 4.05 (dd, J=11.6, 3.2 Hz, 2H), 3.44 (dt, J=12.0, 1.6 Hz,2H), 3.32 (t, J=6.4 Hz, 2H), 2.92-2.76 (m, 1H), 2.34 (s, 1H), 2.09-1.97(m, 1H), 1.82-1.75 (m, 2H), 1.53-1.40 (m, 2H), 0.90-0.84 (m, 2H),0.63-0.58 (m, 1H); MS ESI [M+H]⁺ 498.5, calcd for [C₂₉H₃₁N₅O₃+H]⁺ 498.2.

The following final compounds were synthesized according to thesynthesis of Example B1

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]⁺ Saltform B2: N-cyclopropyl-4-(7-((2- methoxyethyl)amino)-5-phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₅H₂₅N₅O₃ + H]⁺ 444.2; 444.4 308 mg (70%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate(464 mg, 1 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(335 mg, 1.2 mmol), PdCl₂dPPf•DCM (82 mg, 0.1 mmol, 10 mol %); TFA (3mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.29 (s, 1H), 7.91 (d, J = 8.4 Hz,2H), 7.63 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.32-7.26 (m,3H), 6.59 (t, J = 5.2 Hz, 1H), 6.18 (br, s, 1H), 5.68 (s, 1H), 3.72 (t,J = 5.2 Hz, 2H), 3.57 (q, J = 5.3 Hz, 2H), 3.45 (s, 3H), 2.95-2.87 (m,1H), 0.90-0.85 (m, 2H), 0.66-0.60 (m, 2H). B3:N-cyclopropyl-4-(5-phenoxy-7- (((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₉N₅O₃ + H]⁺ 484.2; 484.5 152 mg (52%, 2 steps); off white solid;free base SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth-yl)carbamate (302 mg, 0.6 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide(207 mg, 0.72 mmol), PdCl₂dPPf•DCM (49 mg, 0.06 mmol, 10 mol %); TFA (3mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (s, 1H), 7.90 (d, J = 8.0 Hz,2H), 7.63 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.33-7.26 (m,3H), 6.41 (t, J = 5.8 Hz, 1H), 6.19 (br, s, 1H), 5.68 (s, 1H), 4.08-4.02(m, 214), 3.40 (t, J = 11.2 Hz, 2H), 3.31 (t, J = 6.4 Hz, 2H), 2.95-2.87(m, 1H), 2.09-1.97 (m, 1H), 1.81-1.73 (m, 2H), 1.52-1.40 (m, 2H),0.91-0.85 (m, 2H), 0.66-0.60 (m, 2H). B4: N-cyclopropyl-4-(7-((2-methoxyethyl)amino)-5-(pyridin-3- yloxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

[C₂₄H₂₄N₆O₃ + H]⁺ 445.2; 445.6 133 mg (43%, 2 steps); beige solid; TFAsalt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carb-amate (261 mg, 0.56 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz- amide(178 mg, 0.62 mmol), PdCl₂dppf•DCM (46 mg, 0.056 mmol, 10 mol %); TFA (2mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.91 (d, J = 2.0 Hz, 1H), 8.69 (d, J= 9.2 Hz, 1H), 8.37-8.32 (m, 2H), 7.96 (dd, J = 8.6, 5.4 Hz, 1H), 7.76(d, 3 = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 5.98 (s, 1H), 3.72 (t, J= 5.0 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.44 (s, 3H), 2.88-2.81 (m,1H), 0.85-0.78 (m, 2H), 0.67-0.62 (m, 2H). B5:N-cyclopropyl-2-methyl-4-(7-((2- morpholinoethyl)amino)-5-phenoxypyrazolo[1,5-a]pyrimidin-3- yl)benzamide

[C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.6 2.943 g (68%, 2 steps); light pink solid;TFA salt SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(1.80 g, 3.47 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz-amide (3.14 g, 10.42 mmol), PdCl₂dppf•DCM (142 mg, 0.174 mmol, 5 mol%)-identical two reactions on the same scale; TFA (6 mL). ¹H NMR (400MHz, CDCl₃) δ ppm 8.31 (s, 1H), 7.78 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H),7.48-7.42 (m, 2H), 7.30-7.23 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 5.90 (s,1H), 4.10-3.70 (m, 6H), 3.70-3.10 (m, 6H), 2.87-2.79 (m, 1H), 2.24 (s,3H), 0.83-0.77 (m, 2H), 0.63-0.58 (m, 2H). B6: N-cyclopropyl-4-(7-((2-morpholinoethyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3-yl)benzamide

[C₂₈H₃₀N6O₃ + H]⁺ 499.2; 499.5 56 mg (13%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(0.35 g, 0.68 mmol),N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(215 mg, 0.75 mmol), PdCl₂dppf•DCM (55 mg, 0.07 mmol, 10 mol %); TFA (2mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (s, 1 H), 7.88 (d, 3 = 8.5 Hz,2H), 7.63 (d, J = 8.5 Hz, 2H), 7.50-7.36 (m, 2H), 7.33-7.21 (m, 3H),6.90 (t, J = 4.5 Hz, 1H), 6.33 (br, s, 1H), 5.60 (s, 1H), 3.79 (t, J =4.5 Hz, 4H), 3.44 (q, J = 5.7 Hz, 2H), 2.89 (tq, J = 7.0, 3.5 Hz, 1H),2.80 (t, J = 5.8 Hz, 2H), 2.60 (br, s, 4H), 0.89-0.81 (m, 2H), 0.65-0.57(m, 2H). B7: 2-chloro-N-cyclopropyl-4-(5-phenoxy-7-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈ClN₅O₃ + H]⁺ 518.2; 518.7 141 mg (54%, 2 steps); white solid;free base SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth-yl)carbamate (252 g, 0.5 mmol),(3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (132 g, 0.55 mmol,1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (1 mL). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.23 (s, 1H), 7.96 (s, 1H), 7.73-7.66 (m,2H), 7.48 (t, J = 7.8 Hz, 2H), 7.32-7.26 (m, 3H), 6.49 (br, s, 1H), 6.40(t, J = 6.2 Hz, 1H), 5.72 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 11.6Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 2.97-2.89 (m, 1H), 2.10-1.97 (m, 1H),1.82-1.75 (m, 2H), 1.53-1.41 (m, 2H), 0.91-0.85 (m, 2H), 0.68-0.62 (m,2H). B8: N-cyclopropyl-2-fluoro-4-(5- phenoxy-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈FN₅O₃ + H]⁺ 502.2; 502.5 173 mg (69%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)meth-yl)carbamate (252 g, 0.5 mmol),(4-(cyclopropylcarbamoyl)-3-fluorophenyl)boronic acid (123 g, 0.55 mmol,1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (1 mL). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1H), 8.01 (t, J = 8.4 Hz, 1 H), 7.69(d, J = 14.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz,2H), 7.35-7.26 (m, 3H), 6.85-6.78 (m, 1H), 6.42 (t, J = 6.0 Hz, 1H),5.72 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 11.8 Hz, 2H), 3.33 (t, J =6.4 Hz, 2H), 2.98- 2.90 (m, 1 H), 2.10-1.98 (m, 1H), 1.81-1.75 (m, 2H),1.53-1.41 (m, 2H), 0.91-0.85 (m, 2H), 0.67-0.60 (m, 2H). B9:N-cyclopropyl-2-methyl-4-(5- (pyridin-3-yloxy)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.2 118 mg (39%, 2 steps); brown solid; TFAsalt SMs:tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (232 mg, 0.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv),PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400MHz, CDCl₃) δ ppm 8.98 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 5.3 Hz, 1H),8.26 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 7.9, 5.4 Hz, 1H),7.59-7.51 (m, 2H), 7.29 (s, 1H), 6.61 (t, J = 6.4 Hz, 1H), 6.18 (br, s,1H), 5.78 (s, 1H), 4.07 (dd, J = 11.0,4.0 Hz, 2H), 3.46 (t, J = 11.4 Hz,2H), 3.38 (t, J = 6.5 Hz, 2H), 2.96-2.86 (m, 1H), 2.39 (s, 3H),2.13-2.00 (m, 1 H), 1.85-1.76 (m, 2H), 1.50 (qd, J = 12.2, 4.1 Hz, 2H),0.88 (q, J = 6.3 Hz, 2H), 0.69-0.60 (m, 2H). B10:N-cyclopropyl-4-(5-((2-hydroxy-2- methylpropyl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.3 98 mg (32%, 2 steps); light brown solid;TFA salt SMs: tert-butyl(3-bromo-5-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (249 mg, 0.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (br, s, 1 H), 7.94 (br, s, 1H),7.44-7.19 (m, 4H), 6.90 (br, s, 1H), 6.26 (br, s, 1H), 5.37 (br, s, 1H),4.04 (d, J = 8.8 Hz, 2H), 3.56-3.24 (m, 6H), 3.00-2.86 (m, 1 H), 2.45(s, 3 H), 2.10-1.96 (m, 1 H), 1.73-1.68 (m, 2 H), 1.55-1.41 (m, 2 H),1.34 (s, 6H), 0.96-0.78 (m, 2 H), 0.72-0.57 (m, 2 H). B11:N-cyclopropyl-2-methyl-4-(5- morpholino-7-(((tetrahydro-2H- pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2 68 mg (22%, 2 steps); brown solid; TFAsalt SMs: tert-butyl(3-bromo-5-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (248 mg, 0.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv),PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400MHz, CDCl₃) δ ppm 8.18 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H),7.38 (d, J = 7.8 Hz, 1H), 6.28 (t, J = 6.3 Hz, 1H), 5.97 (br, s, 1H),5.35 (s, 1H), 4.05 (dd, J = 12.0, 3.5 Hz, 2H), 3.91-3.82 (m, 4H),3.74-3.67 (m, 4H), 3.49-3.38 (m, 2H), 3.26 (t, J = 6.3 Hz, 2H),2.97-2.88 (m, 1H), 2.52 (s, 3 H), 2.06-1.92 (m, 1H), 1.79 (d, J = 12.8Hz, 2H), 1.53-1.39 (m, 2H), 0.93-0.84 (m, 2H), 0.67-0.58 (m, 2H). B12:N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-(((tetrahydro-2H- pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₀FN₅O₃ + H]⁺ 516.2; 516.5 130 mg (50%, 2 steps); off white solid;free base SMs: tert-butyl(3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (261 mg, 0.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (166 mg, 0.55 mmol, 1.1 equiv),PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5 mol %); TFA (2 mL). ¹H NMR (400MHz, CDCl₃) δ ppm 8.24 (s, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H),7.41 (dd, J = 15.0, 7.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.10 (d, J =7.6 Hz, 2H), 7.05-6.97 (m, 1H), 6.43 (t, J = 6.4 Hz, 1H), 5.83 (br, s,1H), 5.69 (s, 1H), 4.09-4.02 (m, 2H), 3.44 (t, J = 12.0 Hz, 2H), 3.33(t, J = 6.6 Hz, 2H), 2.93-2.86 (m, 1H), 2.37 (s, 3H), 2.10-1.98 (m, 1H),1.82-1.75 (m, 2H), 1.53-1.42 (m, 2H), 0.91-0.85 (m, 2H), 0.63-0.58 (m,2H). B13: N-cyclopropyl-4-(7-((2- methoxyethyl)amino)-5-phenoxypyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₆H₂₇N₅O₃ + H]⁺ 458.2; 458.4 81 mg (35%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-methoxyethyl)carbamate(232 mg, 0.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(166 mg, 0.55 mmol, 1.1 equiv), PdCl₂dppf•DCM (20.4 mg, 0.025 mmol, 5mol %); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.25 (s, 1H), 7.78 (s,1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.32-7.26 (m,4H), 7.24 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 5.4 Hz, 1H), 5.81 (br, s,1H), 5.70 (s, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H),3.45 (s, 3H), 2.92-2.87 (m, 1H), 2.35 (s, 3H), 0.90-0.85 (m, 2H),0.63-0.57 (m, 2H). B14: 4-(5-(cyclopentylamino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.5 93 mg (38%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (200 mg, 0.41 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (365 mg, 1.21 mmol), PdCl₂dppf•DCM (33mg, 0.040 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.93 (br, s,1H), 7.89 (s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26-7.16 (m, 2 H), 7.03(t, J = 5.6 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 5.11 (s, 1H), 4.05 (dd, J= 11.4, 3.6 Hz, 2H), 3.89 (br, s, 1H), 3.44 (t, J = 11.4 Hz, 2H), 3.35(t, J = 6.3 Hz, 2H), 2.93-2.91 (m, 1H), 2.42 (s, 3 H), 2.04 (m, 3H),1.89-1.60 (m, 8H), 1.54-1.37 (m, 2H), 0.95-0.78 (m, 2H), 0.72-0.58 (m,2H). B15: N-(4-(5-(cyclopentylamino)-7- (((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2-methylphenyl)cyclopropane carboxamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.5 37 mg (14%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (220 mg, 0.44 mmol),N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (200 mg, 0.66 mmol),PdCl₂dppf•DCM (36 mg, 0.044 mmol); TFA (2 mL). ¹H NMR (400 MHz, CDCl₃) δppm 9.29 (br, s, 1H), 8.92 (br, s, 1H), 7.90 (br, s, 1H), 7.76 (br, s,1H), 7.50 (br, s, 1H), 7.33 (br, s, 2H), 7.22 (br, s, 1H), 6.97 (br, s,1H), 5.11 (s, 1H), 4.07 (dd, J = 11.4, 3.6 Hz, 2H), 3.89 (t, J = 5.5 Hz,1H), 3.46 (t, J = 11.5 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 2.31 (br, s,3H), 2.13-1.95 (m, 3), 1.90-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.11 (br,s, 2H), 0.96-0.78 (m, 2H). B16: N-(2-methyl-4-(7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-5- ((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyrimidin-3- yl)phenyl)cyclopropanecarboxamide

[C₂₈H₃₅N₅O₄ + H]⁺ 506.3; 506.5 56 mg (36%, 2 steps); white solid; freebase SMs:tert-butyl(3-bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetra-hydro-2H-pyran-4-yl)methyl)carbamate (160 mg, 0.31 mmol),N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (110 mg, 0.37mmol), PdCl₂dppf•DCM (25 mg, 0.031 mmol); TFA (2 mL). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.21 (s, 1H), 7.93 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.36(d, J = 8.0 Hz, 1H), 6.29 (t, J = 6.1 Hz, 1H), 5.99 (br, s, 1H), 5.47(s, 1H), 5.43-5.33 (m, 1H), 4.11-3.95 (m, 4H), 3.65 (t, J = 9.5 Hz, 2H),3.41 (t, J = 11.7 Hz, 2H), 3.26 (t, J = 6.5 Hz, 2H), 2.97-2.84 (m, 1H),2.51 (s, 3H), 2.27-2.10 (m, 3H), 1.93-1.82 (m, 2H), 1.75 (d, J = 12.3Hz, 2H), 1.51-1.34 (m, 2H), 0.96-0.79 (m, 2H), 0.67-0.54 (m, 2H). B17:N-(2-methyl-4-(5-((tetrahydro-2H- pyran-4-yl)amino)-7-(((tetrahydro-2H-pyran-4-yl) methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)phenyl)cyclopropanecarboxamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.5 35 mg (23%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetra-hydro-2H-pyran-4-yl)methyl)carbamate (72 mg, 0.18 mmol),N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (66 mg, 0.21mmol), PdCl₂dppf•DCM (15 mg, 0.018 mmol); TFA (2 mL). ¹H NMR (400 MHz,CDCl₃) δ ppm 9.65 (br. s, 2H), 7.96 (s, 1H), 7.43-7.30 (m, 3H), 6.83(br, s, 1H), 6.06 (br, s, 1H), 5.08 (s, 1H), 4.13-3.97 (m, 4H), 3.66(br, s, 1H), 3.54 (t, J = 11.0 Hz, 2H), 3.46 (t, J = 11.0 Hz, 2H), 3.35(t, J = 6.4 Hz, 2H), 2.99-2.85 (m, 1 H), 2.48 (s, 3H), 2.12-1.95 (m,3H), 1.93- 1.73 (m, 4H), 1.58-1.42 (m, 2H), 0.94-0.81 (m, 2H), 0.70-0.55(m, 2H). B18: N-(2-methyl-4-(5-phenoxy-7- ((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5- a]pyrimidin-3-yl)phenyl)cyclopropanecarboxamide

[C₂₉H₃₀N₄O₄ + H]⁺ 499.2; 499.5 12 mg (4%, 2 steps); beige solid; freebase SMs:3-bromo-5-phenoxy-7-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine(241 mg, 0.60 mmol),N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (216 mg, 0.72 mmol), PdCl₂dppf•DCM (49 mg, 0.060 mmol). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.33 (br, s, 1 H), 7.74 (br, s, 1 H),7.62-7.42 (m, 3H), 7.39-7.14 (m, 4H), 5.97 (br, s, 1H), 5.85 (br, s,1H), 4.22 (d, J = 6.3 Hz, 2H), 4.07 (d, J = 9.3 Hz, 2H), 3.50 (t, J =11.8 Hz, 2H), 2.89 (br, s, 1H), 2.40 (br, s, 1H), 2.32 (br, s, 3H), 1.90(d, J = 11.5 Hz, 2H), 1.57- 1.45 (m, 2H), 0.87 (d, J = 6.0 Hz, 2H), 0.60(br, s, 2H). B19: N-cyclopropyl-2-methyl-4-(7-((3-morpholinopropyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3-yl)benzamide

[C₃₀H₃₄N₆O₃ + H]⁺ 527.3; 527.3 142 mg (72%, 2 steps); pinkish-whitesolid; TFA salt SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(3-morpholinopropyl)carbamate(200 mg, 0.375 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (124 mg, 1.1 equiv), PdCl₂dppf•DCM (31 mg, 0.0375 mmol, 10mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.82 (s,1H), 7.61 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.35-7.23 (m,3H), 7.18 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 4.14-4.00 (m, 2H),3.84-3.71 (m, 2H), 3.63-3.44 (m, 4H), 3.38-3.27 (m, 4H), 3.23-3.09 (m,2H), 2.88-2.78 (m, 1H), 2.31-2.10 (m, 5H), 0.86-0.74 (m, 2H), 0.65-0.55(m, 2H). B20: N-cyclopropyl-2-methyl-4-(5- phenoxy-7-((2-(tetrahydro-2H-pyran-4- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₃₀H₃₃N₅O₃ + H]⁺ 512.3; 512.2 100 mg (53%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (192 mg, 0.371 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (123 mg, 0.409 mmol), PdCl₂dppf•DCM (30 mg,0.037 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24(s, 1H), 7.78 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41-7.50 (m, 2H),7.32-7.28 (m, 3H), 7.24 (d, J = 7.8 Hz, 1H), 6.24 (t, J = 5.8 Hz, 1H),5.83 (br, s, 1H), 5.67 (s, 1H), 4.00 (dd, J = 11.2, 3.6 Hz, 2H),3.50-3.36 (m, 4H), 2.96-2.83 (m 1H), 2.34 (s, 3H), 1.76 (t, J = 6.5 Hz,3H), 1.68 (d, J = 13.8 Hz, 2H), 1.47-1.34 (m, 2H), 0.92-0.82 (m, 2H),0.60 (br, s, 2H). B21: 4-(5-(cyclopentyloxy)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₈H₃₅N₅O₃ + H]⁺ 490.3; 490.5 70 mg (32%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-(cyclopentyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (224 mg, 0.453 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (150 mg, 0.499 mmol), PdCl₂dppf•DCM (37 mg,0.045 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22(s, 1 H), 7.97 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.0 Hz,1H), 6.24 (t, J = 5.6 Hz, 1H), 5.94 (br, s, 1 H), 5.61-5.51 (m, 1H),5.44 (s, 1H), 4.03 (dd, J = 11.3, 3.3 Hz, 2H), 3.42 (t, J = 11.0 Hz 2H),3.25 (t, J = 6.7 Hz, 2H), 2.98-2.85 (m, 1H), 2.54 (s, 3H), 2.16-1.60 (m,11H), 1.50-1.34 (m, 2H), 0.94-0.83 (m, 2H), 0.63 (br, s, 2H). B22:N-cyclopropyl-2-methyl-4-(5- (pyridin-3-yloxy)-7-((2-(tetrahydro-2H-pyran-4- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.5 92 mg (40%, 2 steps); yellow solid; TFAsalt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (190 mg, 0.367 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (121 mg, 0.403 mmol), PdCl₂dppf•DCM(30 mg, 0.0367 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δppm 8.81 (br, s, 1H), 8.68-8.62 (m, 1H), 8.38 (s, 1H), 8.27-8.20 (m, 1H), 7.91-7.84 (m, 1H), 7.72 (s, 1H), 7.64-7.55 (m, 1H), 7.25-7.17 (m,1H), 5.96 (s, 1H), 4.02-3.91 (m, 2H), 3.54 (t, J = 6.5 Hz, 2H), 3.45 (t,J = 11.3 Hz, 2H), 2.89-2.79 (m, 1H), 2.28 (s, 3H), 1.81- 1.69 (m, 5H),1.44-1.29 (m, 2H), 0.81 (d, J = 6.3 Hz, 2H), 0.61 (br, s, 2H). HPLCpurity: 99.3% at 254 nm. B23: 4-(5-(cyclohexyloxy)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₉H₃₇N₅O₃ + H]⁺ 504.3; 504.5 146 mg (57%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-(cyclohexyloxy)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (281 mg, 0.553 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (183 mg, 0.608 mmol), PdCl₂dppf•DCM (45 mg,0.055 mmol, 10 mol %); TFA (1 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.22(s, 1 H), 8.01 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz,1H), 6.24 (t, J = 6.1 Hz, 1H), 5.93 (br, s, 1H), 5.45 (s, 1H), 5.28-5.12(m, 1H), 4.03 (dd, J = 11.4, 3.6 Hz, 2H), 3.41 (t, J = 12.0 Hz, 2H),3.25 (t, J = 6.4 Hz, 2H), 2.92 (td, J = 7.2, 3.8 Hz, 1H), 2.54 (s, 3H),2.23-2.13 (m, 2H), 2.05-1.92 (m, 1H), 1.91-1.81 (m, 2H), 1.75 (d, J =13.6 Hz, 2H), 1.70-1.22 (m, 8H), 0.90 (q, J = 6.5 Hz 2H), 0.67-0.59 (m,2H). HPLC purity: 95.7% at 254 nm. B24: 4-(5-(cyclohexylamino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-cyclopropyl-2- methylbenzamide

[C₂₉H₃₈N₆O₂ + H]⁺ 503.3; 503.5 61 mg (20%, 2 steps); white solid; TFAsalt SMs: (250 mg, 0.493 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (178 mg, 0.692 mmol), PdCl₂dppf•DCM (40 mg, 0.049 mmol, 10mol %); TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.19 (s, 1H),7.51-7.46 (m, 1H), 7.43 (s, 2H), 4.89 (br, s, 1H), 4.03-3.95 (m, 2H),3.83-3.72 (m, 1H), 3.51-3.42 (m, 4H), 2.93-2.83 (m, 1H), 2.47 (s, 3H),2.12-2.01 (m, 3H), 1.87-1.29 (m, 12H), 0.87-0.80 (m, 2H), 0.67-0.60 (m,2H). HPLC purity: 96.3% at 254 nm. B25:N-cyclopropyl-4-(7-(isobutylamino)- 5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₆H₂₈N₆O₂ + H]⁺ 457.2; 457.4 78 mg (51%, 2 steps); yellow solid; TFAsalt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate(125 mg, 0.27 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (98 mg, 0.32 mmol), PdCl₂dppf•DCM (22 mg, 0.027 mmol, 10mol %); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.84 (s, 1H), 8.67 (d,J = 5.3 Hz, 1H), 8.36 (s, 1H), 8.33-8.27 (m, 1H), 7.95-7.88 (m, 1H),7.68 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.94(s, 1H), 3.30-3.27 (m, 2H), 2.86-2.78 (m, 1H), 2.27 (s, 3H), 2.14-2.05(m, 1H), 1.06 (d, J = 6.8 Hz, 6H), 0.83-0.75 (m, 2H), 0.62-0.55 (m, 2H).B26: N-cyclopropyl-4-(7-(isobutylamino)- 5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin- 3-yl)-2-methylbenzamide

[C₂₆H₃₄N₆O₂ + H]⁺ 463.3; 463.5 43 mg (36%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(isobutyl)carbamate (100 mg, 0.21 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (76 mg, 0.25 mmol), PdCl₂dppf•DCM (17 mg,0.021 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97(s, 1H), 7.42-7.33 (m, 3H), 6.82 (br, s, 1H), 6.03 (br, s, 1H), 5.07 (s,1H), 4.09-4.00 (m, 2H), 3.66 (br, s, 1H), 3.58-3.51 (m, 2H), 3.27 (t, I= 6.4 Hz, 2H), 2.94 (s, 1H), 2.49 (s, 3H), 2.16-2.07 (m, 1H), 2.04-1.94(m, 2H), 1.93-1.80 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.92-0.84 (m, 2H),0.67-0.60 (m, 2H). B27: N-cyclopropyl-4-(7-((2-hydroxy-2-methylpropyl)amino)-5- phenoxypyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide

[C₂₇H₂₉N₅O₃ + H]⁺ 472.2; 472.4 14 mg (15%, 2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (115 mg, 0.20 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (72 mg, 0.24 mmol), PdCl₂dppf•DCM (16 mg,0.02 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s,1H), 7.75 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2 H),7.31-7.25 (m, 4H), 7.22 (d, J = 8.3 Hz, 1H), 6.69-6.62 (m, 1H), 5.85(br, s, 1H), 5.72 (s, 1H), 3.36 (d, J = 6.0 Hz, 2H), 2.89 (br, s, 1H),2.33 (s, 3H), 1.41 (s, 6H), 0.87 (s, 2H), 0.64-0.55 (m, 2H). B28:N-cyclopropyl-4-(7-((2-hydroxy-2- methylpropyl)amino)-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-3- yl)-2-methylbenzamide

[C₂₆H₂₈N₆O₃ + H]⁺ 473.2; 473.4 42 mg (34%, 2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbon-yl)oxy)-2-methylpropyl)carbamate (120 mg, 0.21 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (75 mg, 0.25 mmol),PdCl₂dppf•DCM (17 mg, 0.02 mmol, 10 mol %); TFA (3 mL). ¹H NMR (400 MHz,CD₃OD) δ ppm 8.80-8.76 (m, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H),8.23- 8.16 (m, 1H), 7.88-7.82 (m, 1H), 7.72 (s, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 3.46 (s, 2H), 2.87-2.79(m, 1H), 2.27 (s, 3H), 1.35 (s, 6H), 0.84-0.76 (m, 2H), 0.63-0.56 (m,2H). B29: (R)-N-cyclopropyl-4-(5-((1- hydroxybutan-2-yl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₆N₆O₃ + H]⁺ 493.3 493.5 12 mg (11%, 2 steps); cream solid freebase SMs: (R)-tert-butyl(3-bromo-5-((1-hydroxybutan-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (115 mg, 0.23 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (209 mg, 0.69mmol), PdCl₂dppf•DCM (19 mg, 0.023 mmol, 10 mol %); TFA (3 mL) ¹H NMR(400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 6.4 Hz,1H), 7.32 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 4.11-4.08 (br, s, 1H),3.98-3.95 (m, 2H), 3.75-3.69 (m, 2H), 3.46-3.40 (m, 2H), 3.23 (d, J =6.4 Hz, 2H), 2.88-2.82 (m, 1H), 2.45 (s, 3H), 2.01-1.82 (m, 1H),1.84-1.74 (m, 3H), 1.67-1.60 (m, 1H), 1.43-1.34 (m, 2H), 1.05 (t, J =7.6 Hz, 3H), 0.84-0.79 (m, 2H), 0.63-0.60 (m, 2H). B30:N-cyclopropyl-4-(5-(((2S,3S)-2- hydroxypentan-3-yl)amino)-7-(((tetrahydro-2H-pyran-4-yl)methyl) amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide

[C₂₈H₃₈N₆O₃ + H]⁺ 507.3 507.5 2.25 g, 11% (2 steps); off white solid;free base SMs: tert-butyl(3-bromo-5-(((2S,3S)-2-hydroxypentan-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (9.0 g, 17.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (8.46 g, 28mmol), PdCl₂dppf•DCM (1.35 g, 1.65 mmol, 9.5 mol %), 2M K₃PO₄ (17.6 mL,35 mmol); TFA (14.6 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H),7.98 (s, 1H), 7.89 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H),5.44 (s, 1H), 4.07-3.96 (m, 4H), 3.47-3.41 (m, 2H), 3.24 (d, J = 6.8 Hz,2H), 2.87-2.82 (m, 1H), 2.45 (s, 3H), 2.06-1.99 (m, 11-0, 1.81-1.67 (m,3H), 1.65-1.61 (m, 1H), 1.45-1.34 (m, 2H), 1.22 (d, J = = 6.0 Hz, 3H),1.03 (t, J = 7.2 Hz, 3H), 0.74-0.79 (m, 210, 0.64-0.60 (m, 2H). HPLCPurity: 97.6% at 254 nM B31: N-cyclopropyl-4-(7-((((1r,4r)-4-hydroxycyclohexyl)methyl)amino)- 5-phenoxypyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide

[C₃₀H₃₃N₅O₃ + H]⁺ 512.2; 512.2 49 mg (24%, 2 steps); white solid; freebase SMs:(1r,4r)-4-(((3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)-methyl)cyclohexanol (179 mg, 0.33 mmol) andN-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (99 mg, 0.35 mmol); DCE (12 mL), TFA(5 mL), 80° C., 1 h. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.18 (s, 1 H), 7.70(s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.43-7.35 (m, 2H), 7.25-7.19 (m, 3H),7.17 (d, J = 8.03 Hz, 1H), 6.57-6.49 (m, 1H), 5.60 (s, 1H), 3.58-3.47(m, 1H), 3.26-3.14 (m, 2H), 2.83-2.75 (m, 1H), 2.26 (s, 3H), 2.03-1.95(m, 2H), 1.92-1.84 (m, 2H), 1.76- 1.56 (br, s, 2H), 1.33-1.19 (m, 2H),1.15-1.00 (m, 2H), 0.83-0.74 (m, 2H), 0.60-0.46 (m, 2H); HPLC purity:97.1% at 254 nm. B32: N-cyclopropyl-4-(7-((2-hydroxy-2-methylpropyl)amino)-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.5 78 mg (20%, 2 steps); beige solid; TFAsalt SMs: tert-butyl(3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)carbamate (228 mg, 0.39 mmol),N-cyclopropyl-2-meth-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (141 mg,0.47 mmol), PdCl₂dppf•DCM (32 mg, 0.039 mmol, 10 mol %); TFA (3 mL). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.85 (s, 1H), 7.37-7.27 (m, 3H), 703 (br, s,1H), 6.31 (br, s, 1H), 5.05 (s, 1H), 4.09-3.96 (m, 2H), 3.63 (br, s,1H), 3.56-3.48 (m, 2H), 3.23-3.13 (m, 2H), 2.99-2.86 (m, 1H), 2.45 (s,3H), 2.01-1.92 (m, 2H), 1.83-1.68 (m, 2H), 1.38 (s, 6 H), 0.94-0.83 (m,2H), 0.66-0.59 (m, 2H). B33: N-cyclopropyl-4-(7-((((1r,4r)-4-hydroxycyclohexyl)methyl)amino)- 5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin- 3-yl)-2-methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.2 71 mg (42%, 2 steps) white solid TFA saltSMs: SMs:(1r,4r)-4-(((3-bromo-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(4-methoxybenzyl)amino)methyl)cyclohexanol (0.179 g, 0.328 mmol) andN-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.282g, 1.06 mmol); DCE (22 mL), TFA (5 mL), 80° C., 1 h. ¹H NMR (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.48 (s, 1H), 7.46-7.40 (m, 2H), 5.60 (s,1H), 4.06- 3.95 (m, 3 H), 3.67-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 3.42(d, J = 7.03 Hz, 2 H), 2.92-2.85 (m, 1H), 2.47 (s, 3 H), 2.1-1.97 (m, 4H), 1.86-1.69 (m, 2H), 1.85-1.71 (m, 1 H), 1.71-1.58 (m, 2H), 1.35-1.10(m, 4 H), 0.89-0.79 (m, 2 H), 0.67-0.60 (m, 2 H).

Example C28: Synthesis of tert-butyl tert-butyl(3-bromo-5-phenoxypyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

According to general Method F, using tert-butyl4-(((3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5a]pyrimidin-7-yl)(tert-butoxycarbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylate (7.78 g, 12.2 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(5.14 g, 17.1 mmol), PdCl₂dppfDCM (1.0 g, 1.22 mmol), 2M K₃PO₄ (15 mL,30 mmol) and THF (60 mL) by heating at reflux in an oil bath for 6 h,crude tert-butyl4-(((tert-butoxycarbonyl)(3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-4-fluoropiperidine-1-carboxylate wasobtained as a yellow solid (8.93 g, 100%). MS ESI 677.3 [M-C₄H₈]⁺, calcdfor [C₃₉H₄₆F₂N₆O₆— C₄H₈]⁺ 677.3.

The above compound (8.93 g) was dissolved in DCM (50 mL) and treatedwith TFA (20 mL) at rt for 19 h. After reaction completion, solvent wasremoved in vacuo and the crude was redissolved in DCM (2 mL),neutralized with saturated aqueous sodium bicarbonate and extracted withEtOAc. The combined organic extracts were dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography(gradient: 100% EtOAc then MeOH/DCM 0-20%) using three columns inparallel to giveN-cyclopropyl-4-(5-(3-fluorophenoxy)-7-(((4-fluoropiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamideas a yellow solid (4.25 g, 65% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δppm 9.65-9.45 (m, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=8.0 Hz,1H), 7.46-7.36 (m, 1H), 7.09 (d, J=7.3 Hz, 2H), 7.04-6.94 (m, 1H), 6.62(t, J=6.8 Hz, 1H), 5.86 (br, s, 1H), 5.76 (s, 1H), 3.58 (d, J=6.8 Hz,1H), 3.53 (d, J=6.5 Hz, 1H), 2.99 (dd, J=8.3, 2.8 Hz, 4H), 2.89 (dd,J=7.0, 3.8 Hz, 1H), 2.37 (s, 3H), 2.08-1.94 (m, 2H), 1.80-1.64 (m, 3H),0.94-0.82 (m, 2H), 0.66-0.55 (m, 2H); MS ESI 533.3 [M+H]⁺, calcd for[C₂₉H₃₀F₂N₆O₂+H]⁺ 533.2.

A solution of formaldehyde solution (1 mL, 11.97 mmol, 37 wt. % in H₂O),N-cyclopropyl-4-(5-(3-fluorophenoxy)-7-(((4-fluoropiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenz-amide(4.25 g, 7.98 mmol), and AcOH (1 mL) was stirred at rt for 30 min.NaBH(OAc)₃ (3.38 g, 15.96 mmol) was then added and the resulting mixturewas stirred at rt for 1 h. Sat. NaHCO₃ and DCM were added to separatethe phases and the aqueous phase was extracted with DCM. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by RP flash chromatography (gradient:EtOAc/hex 5-100%) using three columns in parallel, followed by WaterPoraPak Rxn cartridge (three cartridges in parallel) to give the freebase as a white solid (2.13 g, 49%). The free base was dissolved in amixture of DCM (20 mL) and MeOH (40 mL), HCl (4.7 mL, 4.7 mmol, 1M Et₂O)was then added slowly. Solvent was removed in vacuo to give a HCl saltas a pale yellow solid (2.25 g, 49%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.39(s, 1H), 7.84 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54-7.40 (m, 1H), 7.21(d, J=8.0 Hz, 1H), 7.16-6.98 (m, 3H), 6.05 (s, 1H), 3.80 (d, J=18.1 Hz,2H), 3.54 (d, J=12.3 Hz, 2H), 3.29-3.23 (m, 2H), 2.94 (s, 3H), 2.88-2.79(m, 1H), 2.42-2.29 (m, 2H), 2.28 (s, 3H), 2.19 (br, s, 2H), 0.87-0.73(m, 2H), 0.68-0.55 (m, 2H); MS ESI 547.2 [M+H]⁺, calcd for[C₃₀H₃₂F₂N₆O₂+H]⁺ 547.3; HPLC purity: 100% at 254 nm.

Example C29:(S)—N-cyclopropyl-2-methyl-4-(7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-5-(((tetrahydrofuran-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

According to General Method J, to a mixture of(S)-(tetrahydrofuran-2-yl)methanamine (51 mg, 0.5 mmol) and iPr₂NEt(0.175 mL, 1 mmol) was added 0.2 M solution of tert-butyl(3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-5-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamatein NMP (2 mL, 0.4 mmol). The resulting mixture was heated in microwaveat 120° C. for 2 h.

2 mL of H₂O was added to the above reaction and the mixture was heatedin microwave at 140° C. for 2 h. After passing through porapak, it waspurified by RP Biotage C18 column (gradient: CH₃CN/H₂O (0.1% TFA) 0-60%)and porapak to give the title compound as a white solid.

It was redissolved in MeOH (10 mL) and 0.4 mL of 1 M HCl in Et₂O (0.4mmol) was added. After removal of solvents, it was redissolved in MeOHand repeated twice to give the HCl salt of the title compound as lightyellow solid (98.7 mg, 46%). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H),7.55-7.35 (m, 3H), 4.30-4.12 (m, 1H), 4.05-3.35 (m, 10H), 2.92-2.85 (m,1H), 2.47 (s, 3H), 2.20-1.92 (m, 4H), 1.86-1.68 (m, 3H), 1.55-1.38 (m,2H), 0.85-0.78 (m, 2H), 0.70-0.60 (m, 2H); MS ESI 505.3 [M+H]⁺,[C₂₈H₃₆N₆O₃+H]⁺ 505.3; HPLC purity: 98.5% at 254 nm

Example C30:3-((3-(4-(cyclopropylcarbamoyl)-3-methylphenyl)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyridine1-oxide

TheN-cyclopropyl-2-methyl-4-(5-(pyridin-3-yloxy)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide hydrochloride (100 mg, 0.186mmol) was dissolved in MeOH and turned into free base by running throughPoraPak. The resulting free base was dissolved in DCM (4 mL) and wasadded mCPBA (75%, 126 mg, 0.56 mmol) at 0° C. The ice bath was removedand the reaction mixture was stirred at rt for 3.5 h. The solvent wasremoved under reduced pressure and the residue was purified by flashchromatography (MeOH/DCM 0-10%) to give the intermediate as brown solid.¹H NMR (400 MHz, CD₃OD) δ ppm 8.50 (s, 1H), 8.33 (s, 1H), 8.29 (dt,J=4.8, 2.1 Hz, 1H), 7.70 (s, 1H), 7.63-7.56 (m, 3H), 7.22 (d, J=8.0 Hz,1H), 5.87 (s, 1H), 3.97 (dd, J=11.4, 3.1 Hz, 2H), 3.42 (td, J=11.7, 1.9Hz, 2H), 3.31 (d, J=4.8 Hz, 2H), 2.85 (td, J=7.3, 3.6 Hz, 1H), 2.32 (s,3H), 2.01 (d, J=11.8 Hz, 1H), 1.74 (d, J=11.0 Hz, 2H), 1.45-1.32 (m,2H), 0.85-0.77 (m, 2H), 0.65-0.57 (m, 2H). HPLC purity: 99.1% at 254 nm.

The following final compounds were synthesized according to thesynthesis of Example B1 or C28 using General Method F:

MS calcd; Yield; MS ESI Appearance; IUPAC name Structure [M + H]+ Saltform C31: N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-((2-morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₁FN₆O₃ + H]⁺ 531.3; 531.3 3.332 g, 59% (2 steps); white solid; HClsalt SMs: tert-butyl(5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(5.42 g, 10 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.33 g, 21 mmol), PdCl₂dppf•DCM (408 mg, 0.5 mmol, 5 mol%), 2M K₃PO₄ (15 mL, 30 mmol); TFA (10 mL). ¹H NMR (400 MHz, CD₃OD) δppm 8.42 (s, 1H), 7.84 (s, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.53-7.47 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16-7.06 (m, 3H), 6.08 (s, 1H),4.17-4.08 (m, 2H), 3.97 (t, J = 6.2 Hz, 2H), 3.94 (t, J = 11.8 Hz, 2H),3.65 (d, J = 12.0 Hz, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.35-3.27 (m, 2H),2.38-2.31 (m, 3H), 2.27 (s, 3H), 0.84-0.78 (m, 2H), 0.63-0.58 (m, 2H).HPLC purity: 98.9% at 254 nm C32: N-cyclopropyl-4-(5-(2,3-difluorophenoxy)-7-((2- morpholinoethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₀F₂N₆O₃ + H]⁺ 549.2; 549.2 2.84 g, 45% (2 steps); white solid; TFAsalt SMs: tert-butyl(3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (5.31 g, 9.54 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.32 g, 14.31 mmol), PdCl₂dppf•DCM(390 mg, 0.477 mmol, 5 mol %), 2M K₃PO₄ (11.46 mL, 22.92 mmol); TFA (10mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1H), 7.75 (s, 1H), 7.57 (d,J = 8.0 Hz, 1H), 7.29 (t, J = 6.3 Hz, 2H), 7.19 (d, J = 7.3 Hz, 2H),6.14 (s, 1H), 4.18-3.76 (m, 6H), 3.59 (t, J = 5.5 Hz, 4H), 3.42- 3.25(m, 2H), 2.89-2.78 (m, 1H), 2.24 (s, 3H), 0.85-0.76 (m, 2H), 0.66-0.55(m, 2H). HPLC purity: 98.3% at 254 nm C33:2-chloro-N-cyclopropyl-4-(5-(2,3- difluorophenoxy)-7-((2-morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₇ClF₂N₆O₃ + H]⁺ 569.2; 569.3 3.08 g, 51% (2 steps); white solid;HCl salt SMs: tert-butyl(3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate (5.82 g, 10 mmol),(3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid (5.88 g, 24.5mmol), PdCl₂dppf•DCM (272 mg, 0.333 mmol), 2M K₃PO₄ (5 mL, 10 mmol); TFA(10 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1H), 7.99 (d, J = 1.5Hz, 1H), 7.70 (dd, J = 8.0, 1.8 Hz, 1H), 7.29-7.24 (m, 3H), 7.21-7.15(m, 1H), 6.01 (s, 1H), 3.76-3.74 (m, 4H), 3.62 (t, J = 6.3 Hz, 2H), 2.85(tt, J = 7.3, 3.5 Hz, 1H), 2.78 (t, J = 6.3 Hz, 2H), 2.64-2.56 (m, 4H),0.84-0.77 (m, 2H), 0.66- 0.60 (m, 2H). HPLC purity: 98.2% at 254 nm C34:2-chloro-N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-((2-morpholinoethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

[C₂₈H₂₈ClFN₆O₃ + H]⁺ 551.2; 551.2 218 mg, 33% (2 steps); white solid;TFA salt SMs: tert-butyl(5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-morpholinoethyl)carbamate(540 mg, 1 mmol), (3-chloro-4-(cyclopropylcarbamoyl)phenyl)boronic acid(335 mg, 1.4 mmol), PdCl₂dppf•DCM (41 mg, 0.05 mmol, 5 mol %), 2M K₃PO₄(1.5 mL, 3 mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.26 (s,1H), 7.94 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.2, 1.4 Hz, 1H), 7.47-7.41(m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.09-7.00 (m, 3H), 5.90 (s, 1H),4.10-3.80 (m, 6H), 3.70-3.51 (m, 4H), 3.35-3.20 (m, 2H), 2.89-2.83 (m,3H), 0.84-0.78 (m, 2H), 0.67-0.62 (m, 2H). HPLC purity: 97.7% at 254 nmC35: N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7-((((R)-tetrahydrofuran-3- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2-methylbenzamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 4.2 g, 46% (2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(((R)-tetrahydrofuran-3-yl)methyl)carbamate (9.14 g, 17.96 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (8.11 g, 26.94mmol), PdCl₂dppf•DCM (1466 mg, 1.796 mmol, 10 mol %), 2M K₃PO₄ (31 mL,62.85 mmol), THF (100 mL); TFA (18 mL), DCM (18 mL). ¹H NMR (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 8.0, 1.3 Hz, 1H),7.31 (d, J = 8.0 Hz, 1H), 5.45 (d, J = 0.8 Hz, 1H), 4.23-4.11 (m, 2H),3.93 (td, J = 8.2, 5.5 Hz, 1H), 3.85 (m, J = 7.3 Hz, 1H), 3.77 (q, J =7.9 Hz, 1H), 3.65 (dd, J = 8.4, 5.1 Hz, 1H), 3.31-3.28 (m, 2H), 2.90-2.81 (m, 1H), 2.75-2.65 (m, 1H), 2.46 (s, 3H), 2.20-2.07 (m, 1H),1.94-1.61 (m, 7H), 1.48 (d, J = 9.0 Hz, 2H), 0.85-0.78 (m, 2H),0.66-0.60 (m, 2H). HPLC purity: 99.1% at 254 nm C36:N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7-((((S)-tetrahydrofuran-3- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2-methylbenzamide

[C₂₈H₃₆N₆O₃ + H]⁺ 505.2; 505.4 3.10 g, 16% (2 steps); pale yellow solid;free base SMs: tert-butyl(3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(((S)-tetrahydrofuran-3-yl)methyl)carbamate (10.5 g, 20.5 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9.29 g, 30.8mmol), PdCl₂dppf•DCM (1.69 g, 2.05 mmol, 10 mol %), 2M K₃PO₄ (20.6 mL,41.1 mmol); TFA (13 mL). ¹H NMR identical to C8. 402237. HPLC purity:98.3% at 254 nM. C37: N-cyclopropyl-4-(5-(((1S,2R)-2-hydroxycyclohexyl)amino)-7- ((oxetan-3- ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2 75 mg, 69% (2 steps); white solid; freebase SMs: tert-butyl(3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(oxetan-3-ylmethyl)carbamate (338 mg, 0.681 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (226 mg, 0.749 mmol),PdCl₂dppf•DCM (56 mg, 0.068 mmol, 10 mol %), 2M K₃PO₄ (1 mL, 2.04 mmol);TFA (1 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.06 (s, 1H),7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H),4.88-4.83 (m, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.11-4.22 (m, 2H), 3.64 (d,J = 7.3 Hz, 2H), 3.46-3.37 (m, 1H) 2.90-2.81 (m, 1H), 2.46 (s, 3H),1.92-1.62 (m, 6H), 1.54-1.43 (m, 2H), 0.86-0.78 (m, 2H), 0.66-0.60 (m,2H). HPLC purity: 99.2% at 254 nm C38:(S)-N-cyclopropyl-4-(5-((1-hydroxy- 3-methylbutan-2-yl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₈N₆O₃ + H]⁺ 507.3; 507.5 1.98 g, 48% (2 steps); cream solid; freebase SMs: (S)-tert-butyl(3-bromo-5-((1-hydroxy-3-methylbutan-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (6.0 g, 11.7 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (5.28 g, 17.5mmol), PdCl₂dppf•DCM (0.956 g, 1.75 mmol, 10 mol %), 2M K₃PO₄ (11.72 mL,23.4 mmol); TFA (10.5 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H),7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.69 (s, 1H), 3.98 (dd, J = 11.2, 3.2Hz, 2H), 3.84 (br, s, 1H), 3.76-3.68 (m, 2H), 3.46-3.41 (m, 4H),2.91-2.85 (m, 1H), 2.47 (s, 3H), 2.09-2.03 (m, 2H), 1.76-1.73 (m, 2H),1.47-1.37 (m, 2 H), 1.08 (t, J = 7.2 Hz, 6H), 0.86-0.81 (m, 2H),0.65-0.61 (m, 2H). HPLC Purity (HCl salt): 99.0% at 254 nM. C39:N-cyclopropyl-4-(5-(((1S,2R)-2- hydroxycyclohexyl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 1.98 g, 20% (2 steps); cream solid; freebase SMs: tert-butyl(3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.95 g, 15 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.84 g, 23mmol), PdCl₂dppf•DCM (1.21 g, 1.50 mmol, 10 mol %), 2M K₃PO₄ (15.14 mL,30 mmol); TFA (17 mL). ¹H NMR (400 MHz, CD₃Cl₃) δ ppm 8.10 (s, 1H), 7.91(s, 1H), 7.78-7.76 (m, 1H), 7.35 (s, 1H), 7.34 (s, 1H),6.09 (t, J =6.0Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.12 (s, 1H), 4.98 (d, J = 6.8 Hz,1H), 4.20- 4.15 (m, 2H), 4.00 (dd, J = 11.6, 3.6 Hz, 2H), 3.42-3.36 (m,2H), 3.15 (t, J = 6.8 Hz, 2H), 2.93-2.87 (m, 1H), 2.51 (s, 3H),1.97-1.88 (m, 3H), 1.85-1.51 (m, 6H), 1.50-1.41 (m, 2H), 1.39-1.33 (m,2H), 0.90-0.85 (m, 2H), 0.63-0.59 (m, 2H). HPLC Purity (HCl salt): 98.3%at 254 nM. C40: (S)-N-cyclopropyl-4-(5-((2-hydroxy-2,4-dimethylpentan-3- yl)amino)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₄₂N₆O₃ + H]⁺ 535.3; 535.3 1.45 g, 12% (2 steps); cream solid; freebase SMs: (S)-tert-butyl(3-bromo-5-((2-hydroxy-2,4-dimethylpentan-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (5.50 g,10.1 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.59g, 15.2 mmol), PdCl₂dppf•DCM (0.825 g, 1.01 mmol, 10 mol %), 2M K₃PO₄(10.18 mL, 20.2 mmol); TFA (8.4 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18(s, 1H), 8.02 (s, 1H), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 5.53 (s, 1H), 4.33 (s, 1H), 3.92 (dd, J = 11.2, 3.2 Hz, 2H),3.45-3.35 (m, 2H), 3.32-3.31 (m, 1H), 3.18-3.16 (m, 2H), 2.87-2.82 (m,1H), 2.45 (s, 3H), 2.31-2.24 (m, 1H), 1.95-1.85 (m, 1H), 1.85-1.67 (m,2H), 1.37-1.30 (m, 4H), 1.27 (s, 3H), 1.07-1.03 (m, 6H), 0.82-0.78 (m,2H), 0.64-0.60 01, 2H). HPLC Purity (HCl salt): 99.1% at 254 nM. C41:(S)-N-cyclopropyl-4-(5-((1- cyclopropyl-2-hydroxy-2-methylpropyl)amino)-7- (((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 533.4 2.10 g, 17% (2 steps); pale yellow solid;free base SMs: (S)-tert-butyl(3-bromo-5-((1-cyclopropyl-2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate (7.50 g,13.9 mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.27g, 20.8 mmol), PdCl₂dppf•DCM (1.13 g, 1.39 mmol, 10 mol %), 2M K₃PO₄ sol(13.9 mL, 27.8 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.16 (s, 1H), 7.96(s, 1H), 7.77 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.46(s, 1H), 3.96 (dd, J = 11.2, 3.2 Hz, 2H), 3.61-3.58 (m, 1H), 3.41 (t, J= 11.6 Hz, 2 H), 3.22-3.20 (m, 2H), 2.88-2.82 (m, 1H), 2.45 (s, 3H),2.02-1.96 (m, 1H), 1.75-1.72 (m, 2H), 1.42-1.32 (m, 8H), 1.16-1.09 (m,1H), 0.83-0.78 (m, 2H), 0.73-0.68 (m, 1H), 0.64-0.60 (m, 2H), 0.50-0.39(m, 3H). HPLC Purity: 98.2% at 254 nM. C42: N-cyclopropyl-4-(7-((cyclopropylmethyl)amino)-5- (((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo [1,5-a]pyrimidin-3-yl)-2-methylbenzamide

[C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 2.09 g, 25% (2 steps); pale yellow solid;HCl salt SMs: tert-butyl(3-bromo-5-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(cyclopropylmethyl)carbamate (8.48 g, 17.7 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6.92 g, 23.0 mmol),PdCl₂dppf•DCM (1.44 g, 1.76 mmol), 2M K₃PO₄ (26.6 mL, 106.2 mmol); TFA(20 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.51-7.37 (m, 3H),5.67 (br, s, 1H), 4.04-3.82 (m, 2H), 3.46-3.37 (m, 2H), 2.93-2.82 (m,1H), 2.47 (s, 3H), 1.89-1.64 (m, 6H), 1.61-1.42 (m, 2H), 1.31- 1.21 (m,1H), 0.88-0.78 (m, 2H), 0.70-0.58 (m, 4H), 0.46-0.36 (m, 2H). HPLCpurity: 98% at 254 nm. C43: N-cyclopropyl-4-(7-((((1s,3s)-3- hydroxy-3-methylcyclobutyl)methyl)amino)-5- (pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.3 96 mg, 47% (2 steps); beige solid; HClsalt SMs: tert-butyl(3-bromo-5-(pyridin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.23 g, 0.38mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.15 g,0.49 mmol), PdCl₂dppf•DCM (0.031 g, 0.038 mmol), 2M K₃PO₄ (0.57 mL, 1.14mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 9.14 (br, s, 1H),8.89-8.82 (m, 1H), 8.79-8.71(m, 1H), 8.40 (s, 1H), 8.31-8.21 (m, 1H),7.68 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.06(s, 1H), 3.56 (d, J = 6.5 Hz, 2H), 2.88-2.79 (m, 1H), 2.40-2.31 (m, 1H),2.29 (s, 3H), 2.26-2.18 (m, 2H), 1.99- 1.89 (m, 2H), 1.37 (s, 3H),0.85-0.76 (m, 2H), 0.63-0.53 (m, 2H). HPLC purity: 99.5% at 254 nm. C44:4-(5-(cyclopentylamino)-7- ((((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)amino) pyrazolo[1,5-a]pyrimidin-3-yl)-N-cyclopropyl-2-methylbenzamide

[C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.4 75 mg, 21% (2 steps); light orange solid;HCl salt SMs: tert-butyl(3-bromo-5-(cyclopentylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(((1s,3s)-3-((tert-butoxycarbonyl)oxy)-3-methylcyclobutyl)methyl)carbamate (0.40 g, 0.67mmol), N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.26 g,0.88 mmol), PdCl₂dppf•DCM (0.055 g, 0.067 mmol), 2M K₃PO₄ (1 mL, 2.01mmol); TFA (3 mL). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.18 (s, 1H), 7.42 (s,3H), 5.52 (br, s, 1H), 4.23-4.11 (m, 1H), 3.68-3.54 (m, 2H), 2.93-2.81(m, 1H), 2.46 (s, 3H), 2.38-2.27 (m, 1H), 2.26-2.07 (m, 4H), 1.99-1.89(m, 2H), 1.88-1.59 (m, 6H), 1.35 (s, 3H), 0.86-0.79 (m, 2H), 0.66-0.58(m, 2H). HPLC purity: 99% at 254 nm. C45: N-cyclopropyl-4-(5-((1-(hydroxymethyl)cyclopentyl)amino)- 7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.5 83 mg, 16 mg (2 steps); white solid; TFAsalt SMs:tert-butyl(3-bromo-5-((1(hydroxymethyl)cyclopentyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)((tetrahydro-2H-pyran-4-yl) methyl)carbamate (437 mg, 0.83 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (350 mg, 1.2mmol), PdCl₂dppf•DCM (68 mg, 0.0.083 mmol), and 2 M K₃PO₄ (1.3 mL, 2.5mmol); TFA (6 mL). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (br, s, 1H), 7.94(s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.26-7.20 (m, 2H), 6.78 (br, s, 1H),5.73 (br, s, 1H), 3.97 (dd, J = 11.2, 3.4 Hz, 2H), 3.66 (s, 2H), 3.37(t, J = 11.2 Hz, 2H), 3.19 (t, J = 5.9 Hz, 2H), 2.92-2.79 (m, 1H), 2.44(s, 3H), 2.04-1.53 (m, 11H), 1.43-1.23 (m, 2H), 0.91-0.75 (m, 2H),0.70-0.56 (m, 2H). HPLC purity: 99.5% at 254 nm C46:N-cyclopropyl-4-(5-(3- fluorophenoxy)-7-(((1- methylpiperidin-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2- methylbenzamide

[C₃₀H₃₃FN₆O₂ + H]⁺ 529.3 529.3 116 mg, 29% (2 steps); off white powder;TFA salt SMs: tert-butyl(3-bromo-5-(3-fluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)((1-methylpiperidin-4-yl)methyl)carbamate (0.338, 0.63 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.381 g, 1.3 mmol) ¹H NMR (400 MHz, CD₃OD)δ ppm 8.39 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.53-7.45(m, 1H), 7.21 (d, J = 7.80 Hz, 1H), 7.14-7.04 (m, 3H), 5.95 (s, 1H),3.61-3.54 (m, 2H), 3.46 (d, J = 6.0 Hz, 2H), 3.09-2.98 (m, 2H), 2.89 (s,3H), 2.86-2.79 (m, 1H), 2.28 (s, 3H), 2.10-2.22 (m, 3H), 1.66-1.48 (m,2H), 0.84-0.72 (m, 2H), 0.67-0.55 (m, 2H). HPLC Purity (HCl salt): 97.7%at 254 nM C47: N-cyclopropyl-4-(5-(2,3- difluorophenoxy)-7-((2-(4-fluoropiperidin-1- yl)ethyl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-2-methylbenzamide

[C₃₀H₃₁F₃N₆O₂ + H]⁺ 565.2 565.4 86 mg, 23% (2 steps); white powder; TFAsalt SMs: tert-butyl(3-bromo-5-(2,3-difluorophenoxy)pyrazolo[1,5-a]pyrimidin-7-yl)(2-(4-fluoropiperidin-1-yl)ethyl)carbamate (315 mg, 0.55 mmol),N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.244 g, 0.81 mmol) ¹HNMR (400 MHz, CDCl₃) δ ppm 8.20 (s, 1H), 7.66 (s, 1H), 7.46 (d, J = 6.5Hz, 1H), 7.33 (br. s., 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.19-7.08 (m, 3H),5.99 (d, J = 2.5 Hz, 1H), 5.10-4.93 (m, 1H), 3.94 (q, J = 5.8 Hz, 2H),3.64 (br. s., 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.15 (br. s., 2H),2.95-2.85 (m, 1H), 2.45-2.15 (m, 4H), 2.30 (s, 3H), 0.99-0.82 (m, 2H),0.67-0.57 (m, 2H). HPLC Purity: 99.7% at 254 nM

The following final compounds were synthesized according to thesynthesis of Example B1, C28 or C29 using General Method F or J:

Example number MS calcd; MS ESI [M + H]⁺ Salt Form; Structure HPLCpurity ¹H NMR

C48 [C₂₉H₃₈N6O₃ + H]⁺ 519.3; 519.5 TFA salt; 93.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 7.52-7.36 (m, 3H), 5.58 (s, 1H), 3.99 (dd, J= 11.2, 3.4 Hz, 2H), 3.81-3.71 (m, 1H), 3.70-3.60 (m, 1H), 3.52- 3.39(m, 4H), 2.87 (dq, J = 7.3, 3.7 Hz, 1H), 2.46 (s, 3H), 2.18-1.95 (m,5H), 1.75 (d, J = 12.3 Hz, 2H), 1.59-1.36 (m, 6H), 0.87-0.77 (m, 2H),0.67- 0.59 (m, 2H).

C49 [C₂₈H₃₁N₇O₂ + H]⁺ 498.3; 498.4; di-TFA salt; 99.4% at 254 nm (400MHz, CD₃OD) δ ppm 8.92 (br, s, 1H), 8.80 (d, J = 5.5 Hz, 1H), 8.63-8.52(m, 1H), 8.23 (s, 1H), 8.07-7.96 (m, 1H), 7.73-7.45 (m, 2H), 7.38 (d, J= 8.0 Hz, 1H), 5.55 (s, 1H), 3.96 (d, J = 11.8 Hz, 3H), 3.61-3.49 (m,2H), 3.36-3.29 (s, 2H), 2.88 (tt, J = 7.3, 3.8 Hz, 1H), 2.46 (s, 3H),1.98 (d, J = 12.0 Hz, 2H), 1.67-1.50 (m, 2H), 0.88-0.78 (m, 2H),0.68-0.60 (m, 2H).

C50 [C₂₈H₃₀N₆O₃ + H]⁺ 499.3; 499.5; TFA salt; 98.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.97 (d, J = 7.8 Hz, 1H), 8.57-8.55 (m, 1H), 8.01-7.97 (m,1H), 7.94 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H),6.59 (s, 1H), 3.99 (dd, J = 11.0, 3.3 Hz, 2H), 3.51-3.41 (m, 5H), 2.88(tt, J = 7.3, 3.8 Hz, 1H), 2.47 (s, 3H), 2.16-2.07 (m, 1H), 1.83-1.76(m, 2H), 1.51-1.39 (m, 2H), 0.87-0.80 (m, 2H), 0.66-0.62 (m, 2H).

C51 [C₂₈H₃₁N₇O₃ + H]⁺ 514.3; 514.2 di-TFA salt: 98% at 254 nm (400 MHz,CD₃OD) δ ppm 8.73 (br, s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H),8.11 (d, J = 7.8 Hz, 1H), 7.84-7.77 (m, 1H), 7.72 (s, 1H), 7.60 (d, J =7.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 4.19-3.77 (m, 6H),3.73-3.51 (m, 4H), 3.25-3.41 (m, 2H), 2.88-2.80 (m, 1H), 2.28 (s, 3H),0.88-0.74 (m, 2H), 0.66-0.56 (m, 2H).

C52 [C₂₈H₃₀N₆O₃ + H]⁺ 499.3; 499.2 TFA salt; 96.7% at 254 nm (400 MHz,CD₃OD) δ ppm 8.91 (s, 1H), 8.79 (d, J = 5.8 Hz, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.39 (s, 1H), 8.06 (dd, J = 8.0, 5.8 Hz, 1H), 8.02 (s, 1H),7.86 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.58 (s, 1H), 5.34(tt, J = 8.5, 4.3 Hz, 1H), 4.89 (s, 2H), 3.97 (dt, J = 11.6, 4.5 Hz,2H), 3.63 (ddd, J = 11.6, 9.2, 2.5 Hz, 2H), 2.87 (tt, J = 7.3, 3.7 Hz,1H), 2.45 (s, 3H), 2.20-2.12 (m, 2H), 1.84-1.72 (m, 2H), 0.86-0.79 (m,2H), 0.66-0.61 (m, 2H).

C53 [C₂₈H₃₇N₇O₃ + H]⁺ 520.3; 502.3 di-TFA salt; 98.1% at 254 nm (400MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.79-7.65 (m, 1H), 7.64-7.53 (m, 1H),7.38 (d, J = 7.3 Hz, 1H), 5.65 (br, s, 1H), 4.18-3.82 (m, 8H), 3.70-3.50(m, 5H), 3.22-3.42 (m, 4H), 2.92-2.82 (m, 1H), 2.46 (s, 3H), 2.16-2.03(m, 2H), 1.72-1.58 (m, 2H), 0.89-0.78 (m, 2H), 0.68-0.60 (m, 2H).

C54 [C₂₉H₃₀F₂N₆O₃ + H]⁺ 549.2; 549.2 TFA salt; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.84 (d, J = 5.5 Hz, 2H), 8.27 (s, 1H), 8.08 (d, J = 6.8Hz, 2H), 7.77- 7.65 (m, 1H), 7.64-7.54 (m, 1H), 7.39 (d, J = 8.0 Hz,1H), 5.54-5.41 (m, 1H), 5.08 (br, s, 2H), 4.01-3.90 (m, 3H), 3.53 (td, J= 11.4, 2.0 Hz, 2H), 2.88 (tt, J = 7.3, 3.8 Hz, 1H), 2.47 (s, 3H),2.02-1.93 (m, 2H), 1.64-1.51 (m, 2H), 0.88- 0.80 (m, 2H), 0.67-0.61 (m,2H).

C55 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.2 TFA salt; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.38-7.54 (m, 3H), 5.50 (s, 1H), 4.12-4.03(m, 1H), 3.99 (dd, J = 10.9, 4.1 Hz, 2H), 3.49-3.39 (m, 4H), 2.88 (tt, J= 7.4, 3.8 Hz, 1H), 2.47 (s, 3H), 2.13-2.00 (m, 1H), 1.79-1.71 (m, 2H),1.50-1.38 (m, 2H), 1.35 (d, J = 6.5 Hz, 6H), 0.88-0.79 (m, 2H),0.67-0.61 (m, 2H).

C56 [C₂₈H₂₉FN₆O₃ + H]⁺ 517.2; 517.2 free base; 97.9% at 254 nm ¹H NMR(400 MHz, CDCl₃) δ ppm 8.50 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.3 Hz,1H), 8.26 (s, 1H), 7.72 (s, 1H), 7.61-7.55 (m, 2H), 7.30-7.28 (m, 1H),6.54-6.49 (m, 1H), 5.85 (br, s, 1H), 5.75 (s, 1H), 4.06 (dd, J = 10.9,4.1 Hz, 2H), 3.45 (td, J = 12.0, 2.1 Hz, 2H), 3.36 (t, J = 6.5 Hz, 2H),2.93-2.87 (m, 1H), 2.40 (s, 3H), 2.12-1.99 (m, 1H), 1.80 (d, J = 11.0Hz, 2H), 1.50 (td, J = 12.1, 3.9 Hz, 2H), 0.92- 0.84 (m, 2H), 0.65-0.58(m, 2H).

C57 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 96.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.37 (m, 3H), 4.05-3.94 (m, 4H),3.51-3.35 (m, 8H), 2.88 (tt, J = 7.3, 3.7 Hz, 1H), 2.47 (s, 3H), 2.13-1.91 (m, 2H), 1.81-1.72 (m, 4H), 1.43 (qd, J = 12.3, 4.6 Hz, 4H),0.88-0.80 (m, 2H), 0.67-0.61 (m, 2H).

C58 [C₂₉H₃₈N₆O₂ + H]⁺ 503.3; 503.3 free base; 98.2% at 254 nm (400 MHz,CDCl₃) δ ppm 8.15 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.37(d, J = 8.3 Hz, 1H), 6.11 (t, J = 5.8 Hz, 1H), 5.94 (br, s, 1H), 5.29(s, 1H), 5.05 (t, J = 8.4 Hz, 1H), 4.04 (dd, J = 11.4, 3.6 Hz, 2H), 3.43(td, J = 11.8, 2.0 Hz, 2H), 3.25 (t, J = 6.3 Hz, 2H), 3.03 (s, 3H), 2.92(tq, J = 6.9, 3.7 Hz, 1H), 2.53 (s, 3H), 2.17-2.05 (m, 2H), 2.05-1.94(m, 2H), 1.84-1.75 (m, 4H), 1.74- 1.59 (m, 3H), 1.53-1.39 (m, 2H),0.92-0.84 (m, 2H), 0.66-0.59 (m, 2H).

C59 [C₂₈H₃₁N₇O₂ + H]⁺ 498.3; 498.4 TFA salt; 98% at 254 nm (400 MHz,CD₃OD) δ ppm 9.69 (br, s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.38 (d, J =5.5 Hz, 1H), 8.32 (s, 1H), 7.96 (dd, J = 8.9, 5.9 Hz, 1H), 7.82-7.86 (m,2H), 7.41 (d, J = 7.8 Hz, 1H), 5.68 (s, 1H), 4.00 (dd, J = 11.3, 3.8 Hz,2H), 3.45 (t, J = 10.8 Hz, 2H), 3.37-3.27 (m, 2H), 2.89 (tt, J = 7.3,3.9 Hz, 1H), 2.48 (s, 3H), 2.10-2.04 (m, 1H), 1.80-1.78 (m, 2H),1.48-1.38 (m, 2H), 0.69-0.84 (m, 2H), 0.62- 0.69 (m, 2H).

C60 [C₂₉H₃₃N₇O₂ + H]⁺ 512.3; 512.2 TFA salt; 99.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.32 (s, 1H), 8.15 (s, 1H), 7.84-7.80 (m, 3H), 7.40-7.34(m, 3H), 7.09- 7.05 (m, 1H), 5.68 (s, 1H), 4.15-3.95 (m, 2H), 3.85 (br,s, 4H), 3.56 (br, s, 4H), 3.37-3.26 (m, 2H), 2.90-2.86 (m, 1H), 2.49 (s,3H), 0.86-0.81 (m, 2H), 0.69-0.61 (m, 2H).

C61 [C₂₉H₂₉N₇O₂ + H]⁺ 508.2; 508.2 free base; 97.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.32 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J =7.9, 1.4 Hz, 1H), 7.49-7.41 (m, 2H), 7.32-7.23 (m, 3H), 7.21-7.15 (m,2H), 7.03 (s, 1H), 5.68 (s, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.37 (t, J =6.9 Hz, 2H), 2.83 (tt, J = 7.3, 3.7 Hz, 1H), 2.24 (s, 3H), 2.20 (t, J =7.0 Hz, 2H), 0.83-0.76 (m, 2H), 0.63-0.57 (m, 2H).

C62 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 free base; 97.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H),7.29 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 4.32 (quint, J = 6.3 Hz, 1H),4.16 (qd, J = 6.8, 4.4 Hz, 1H), 3.95-3.86 (m, 1H), 3.81-3.73 (m, 1H),3.43-3.36 (m, 1H), 3.31- 3.25 (m, 1H), 2.85 (tt, J = 7.3, 3.7 Hz, 1H),2.44 (s, 3H), 2.19-1.86 (m, 5H), 1.84-1.52 (m, 7H), 0.84-0.77 (m, 2H),0.66-0.60 (m, 2H).

C63 [C₂₇H₃₄N₆O₂ + H]⁺ 491.3; 491.3 free base; 99.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.30(d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 4.24-4.12 (m, 2H), 4.06-3.98 (m, 2H),3.97-3.88 (m, 1H), 3.83-3.75 (m, 1H), 3.60 (td, J = 11.5, 2.0 Hz, 2H),3.47-3.39 (m, 1H), 3.37- 3.32 (m, 1H), 2.86 (tt, J = 7.3, 3.9 Hz, 1H),2.45 (s, 3H), 2.19-1.87 (m, 5H), 1.75 (s, 1H), 1.60 (dd, J = 12.7, 4.4Hz, 2H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C64 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.3 free base; 98.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H),7.29 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 4.32 (quint, J = 6.3 Hz, 1H),4.16 (qd, J = 6.8, 4.4 Hz, 1H), 3.95-3.86 (m, 1H), 3.81-3.73 (m, 1H),3.43-3.36 (m, 1H), 3.31- 3.25 (m, 1H), 2.85 (tt, J = 7.3, 3.7 Hz, 1H),2.44 (s, 3H), 2.19-1.86 (m, 5H), 1.84-1.52 (m, 7H), 0.84-0.77 (m, 2H),0.66-0.60 (m, 2H).

C65 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.3 free base; 98.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.30(d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 4.24-4.12 (m, 2H), 4.06-3.98 (m, 2H),3.97-3.88 (m, 1H), 3.83-3.75 (m, 1H), 3.60 (td, J = 11.5, 2.0 Hz, 2H),3.47-3.39 (m, 1H), 3.37- 3.32 (m, 1H), 2.86 (tt, J= 7.3, 3.9 Hz, 1H),2.45 (s, 3H), 2.19-1.87 (m, 5H), 1.75 (s, 1H), 1.60 (dd, J = 12.7, 4.4Hz, 2H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C66 [C₃₀H₃₈N₆O₃ + H]⁺ 531.3; 531.6 free base; 98.5% at 254 nm (400 MHz,CDCl₃) δ ppm 8.15 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.37(d, J = 7.8 Hz, 1H), 6.08 (t, J = 6.0 Hz, 1H), 5.92 (br, s, 1H), 4.60(br, s, 2H), 4.13 (s, 1H), 4.04 (dd, J = 11.0, 3.3 Hz, 2H), 3.43 (td, J= 11.9, 1.9 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 2.91 (td, J = 7.1, 3.4Hz, 1H), 2.53 (s, 3H), 2.41-2.30 (m, 4H), 2.16-2.09 (m, 2H), 2.03- 1.92(m, 1H), 1.79 (d, J = 14.6 Hz, 4H), 1.52-1.38 (m, 2H), 0.92-0.85 (m,2H), 0.65-0.59 (m, 2H).

C67 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3 free base; 98.5% at 254 nm (400 MHz,CDCl₃ & drops of CD₃OD) δ ppm 8.12 (s, 1H), 7.89-7.84 (m, 2H), 7.34 (d,J = 8.5 Hz, 1H), 5.37 (s, 1H), 4.22-4.13 (m, 2H), 4.01 (dd, J = 11.2,3.9 Hz, 2H), 3.97-3.90 (m, 1H), 3.46-3.37 (m, 2H), 3.30 (ddd, J = 13.2,9.9, 3.0 Hz, 2H), 3.21 (d, J = 6.8 Hz, 2H), 2.82-2.90 (m, 1H), 2.48 (s,3H), 2.03-1.93 (m, 3H), 1.81-1.73 (m, 2H), 1.66-1.54 (m, 2H), 1.49-1.36(m, 2H), 0.90-0.81 (m, 2H), 0.59 (d, J = 2.5 Hz, 2H).

C68 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.2 free base; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.2, 1.6 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.44 (quint, J = 7.0 Hz, 1H),3.98 (dd, J = 11.4, 3.6 Hz, 2H), 3.56 (d, J = 7.8 Hz, 2H), 3.40-3.45 (m,2H), 3.23 (d, J = 7.0 Hz, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H), 2.62-2.52(m, 1H), 2.45 (s, 3H), 2.27-2.19 (m, 2H), 2.13-1.96 (m, 3H), 1.80-1.73(m, 2H), 1.46-1.34 (m, 2H), 0.85-0.79 (m, 2H), 0.66- 0.61 (m, 2H).

C69 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.2 free base; 99.8% at 254 nm (400 MHz,CDCl₃) δ ppm 8.13 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.33(d, J = 8.0 Hz, 1H), 6.12 (t, J = 5.9 Hz, 1H), 5.98 (br. s., 1H), 4.95(s, 1H), 4.83-4.75 (m, 1H), 4.38 (dd, J = 9.2, 6.9 Hz, 2H), 4.03 (dd, J= 11.7, 3.9 Hz, 2H), 3.97 (dd, J = 9.5, 4.3 Hz, 2H), 3.42 (td, J = 11.9,1.9 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.90 (tq, J = 7.1, 3.7 Hz, 1H),2.50 (s, 3H), 1.89-2.02 (m, 1H), 1.76 (d, J = 13.1 Hz, 2H), 1.64 (br, s,1H), 1.50-1.37 (m, 2H), 0.92-0.84 (m, 2H), 0.65- 0.58 (m, 2H).

C70 [C₂₈H₃₄N₈O + H]⁺ 499.3; 499.2 free base; 97.4% at 254 nm (400 MHz,CDCl₃) δ ppm 8.12 (s, 1H), 7.96 (s, 1H), 7.85 (dd, J = 8.2, 1.1 Hz, 1H),7.46 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.92 (s, 1H),6.13-5.98 (m, 2H), 4.99-4.91 (m, 2H), 4.22 (d, J = 5.8 Hz, 1H), 4.08 (t,J = 6.7 Hz, 2H), 3.21 (q, J = 6.5 Hz, 2H), 2.90 (tq, J = 7.1, 3.6 Hz,1H), 2.50 (s, 3H), 2.20-2.07 (m, 4H), 1.82-1.60 (m, 4H), 1.54 (dq, J =12.7, 6.6 Hz, 2H), 0.90-0.82 (m, 2H), 0.65- 0.57 (m, 2H).

C71 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.4 free base; 98.2% at 254 nm (400 MHz,DMSO-d₆) δ ppm 8.33 (s, 1H), 8.17 (d, J = 4.3 Hz, 1H), 8.01-7.97 (m,1H), 7.92 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 5.5 Hz, 1H), 7.26 (d, J =8.0 Hz, 1H), 7.10 (t, J = 5.4 Hz, 1H), 5.33 (s, 1H), 4.67 (dd, J = 7.7,5.9 Hz, 2H), 4.39 (t, J = 5.9 Hz, 2H), 3.85 (dd, J = 10.7, 2.9 Hz, 2H),3.67 (t, J = 6.3 Hz, 2H), 3.30- 3.22 (m, 3H), 3.12 (t, J = 6.5 Hz, 2H),2.85- 2.76 (m, 1H), 2.36 (s, 3H), 2.00-1.86 (m, 1H), 1.60(d, J = 12.0Hz, 2H), 1.30-1.16 (m, 2H), 0.69-0.62 (m, 2H), 0.52 (m, 2H).

C72 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4 free base; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.16 (s, 1H), 8.09 (s, 1H), 7.88 (dd, J = 8.2, 1.4 Hz, 1H),7.29 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 4.37-4.27 (m, 1H), 3.90 (td, J =8.2, 5.4 Hz, 1H), 3.82 (dd, J = 8.8, 6.8 Hz, 1H), 3.70-3.77 (m, 1H),3.62 (dd, J = 8.8, 5.0 Hz, 1H), 3.24 (d, J = 7.3 Hz, 2H), 2.88-2.81 (m,1H), 2.71-2.58 (m, 1H), 2.43 (s, 3H), 2.18-2.04 (m, 3H), 1.84-1.49 (m,7H), 0.85-0.77 (m, 2H), 0.65-0.59 (m, 2H).

C73 [C₂₉H₃₃N₇O₃ + H]⁺ 512.3; 512.4 free base; 97.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.51 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 7.83 (s, 1H),7.71-7.79 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.30-7.24 (m, 1H), 7.22 (d,J = 8.0 Hz, 1H), 5.44 (s, 1H), 4.77 (s, 2H), 3.94 (dd, J = 11.0, 3.8 Hz,2H), 3.37 (d, J = 12.0 Hz, 2H), 3.23-3.14 (m, 2H), 2.84 (tt, J = 7.3,3.8 Hz, 1H), 2.34 (s, 3H), 2.00-1.87 (m, 1H), 1.75-1.64 (m, 2H),1.41-1.26 (m, 2H), 0.84-0.76 (m, 2H), 0.66- 0.57 (m, 2H).

C74 [C₂₉H₃₃N₇O₂ + H]⁺ 512.3; 512.4 free base; 98.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.64 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 4.8, 1.5 Hz, 1H),8.18 (s, 1H), 7.91 (dt, J = 7.9, 1.8 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J= 8.2, 1.6 Hz, 1H), 7.39 (dd, J = 8.4, 4.9 Hz, 1H), 7.27 (d, J = 8.0 Hz,1H), 5.40 (s, 1H), 4.71 (s, 2H), 3.96 (dd, J = 11.0, 3.5 Hz, 2H), 3.41(td, J = 11.9, 1.9 Hz, 2H), 3.21 (d, J = 7.0 Hz, 2H), 2.84 (tt, J = 7.4,3.8 Hz, 1H), 2.38 (s, 3H), 2.05-1.91 (m, 1H), 1.77-1.69 (m, 2H),1.44-1.30 (m, 2H), 0.85- 0.77 (m, 2H), 0.65-0.60 (m, 2H).

C75 [C₂₉H₃₄N₈O₂ + H]⁺ 527.3; 527.4 free base; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.64 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 5.0, 1.5 Hz, 1H),8.19 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J = 8.0,1.5 Hz, 1H), 7.38 (dd, J = 7.9, 4.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H),5.41 (s, 1H), 4.71 (s, 2H), 3.74 (t, J = 4.6 Hz, 4H), 3.45 (t, J = 6.4Hz, 2H), 2.85 (tt, J = 7.4, 3.8 Hz, 1H), 2.77 (t, J = 6.1 Hz, 2H), 2.61(br, s, 4H), 2.38 (s, 3H), 0.85-0.78 (m, 2H), 0.66-0.59 (m, 2H).

C76 [C₂₇H₃₅N₇O₂ + H]⁺ 490.3; 490.4 free base; 97.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 8.03 (s, 1H), 7.92 (dd, J = 8.2, 1.4 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 5.38-5.34 (m, 1H), 3.71-3.78 (m, 4H),3.48-3.40 (m, 2H), 3.36-3.33 (m, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H),2.70-2.75 (m, 2H), 2.60-2.52 (m, 4H), 2.45 (s, 3H), 1.26-1.15 (m, 1H),0.86-0.78 (m, 2H), 0.66-0.60 (m, 2H), 0.58-0.52 (m, 2H), 0.35- 0.29 (m,2H).

C77 [C₂₈H₃₇N₇O₂ + H]⁺ 504.3; 504.4 free base; 95.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 8.10 (s, 1H), 7.90 (dd, J = 7.9, 1.4 Hz, 1H),7.31 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 4.35 (quint, J = 6.5 Hz, 1H),3.76-3.71 (m, 4H), 3.42 (t, J = 6.4 Hz, 2H), 2.85 (tt, J = 7.3, 3.8 Hz,1H), 2.71 (t, J = 6.4 Hz, 2H), 2.52-2.58 (m, 4H), 2.45 (br, s, 3H),2.20- 2.08 (m, 2H), 1.86-1.51 (m, 6H), 0.86-0.78 (m, 2H), 0.66-0.60 (m,2H).

C78 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.4 free base; 99.1% at 254 nm (400 MHz,CD₃OD) δ ppm 8.17 (s, 1H), 8.10 (s, 1H), 7.86 (dd, J = 8.2, 1.6 Hz, 1H),7.31 (d, J = 8.3 Hz, 1H), 5.50 (s, 1H), 4.31 (br, s, 1H), 4.01-3.92 (m,3H), 3.59 (dd, J = 11.2, 8.4 Hz, 1H), 3.44 (td, J = 11.8, 1.8 Hz, 2H),3.26-3.20 (m, 2H), 2.86 (tt, J = 7.4, 3.8 Hz, 1H), 2.47 (s, 3H),2.08-1.96 (m, 1H), 1.80-1.73 (m, 2H), 1.46-1.32 (m, 2H), 1.07 (s, 9H),0.85-0.79 (m, 2H), 0.66-0.60 (m, 2H).

C79 [C₂₈H₃₆N₆O₄ + H]⁺ 521.3; 521.3 free base; 98.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 8.04-8.02 (m, 1H), 7.89 (dd, J = 8.2, 1.4 Hz,1H), 7.33 (d, J = 8.0 Hz, 1H), 5.42 (d, J = 1.5 Hz, 1H), 4.26 (dd, J =11.0, 4.8 Hz, 1H), 4.09-4.01 (m, 1H), 4.01-3.95 (m, 3H), 3.76 (td, J =9.2, 4.8 Hz, 1H), 3.52 (td, J = 11.2, 2.5 Hz, 1H), 3.43 (t, J = 11.4 Hz,2H), 3.26- 3.20 (m, 3H), 2.89-2.81 (m, 1H), 2.46 (s, 3H), 2.12-1.97 (m,2H), 1.79-1.66 (m, 3H), 1.46-1.33 (m, 2H), 0.85-0.79 (m, 2H), 0.66-0.60(m, 2H).

C80 [C₂₅H₃₂N₆O₂ + H]⁺ 449.3; 449.3 free base; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.30(d, J = 8.0 Hz, 1H), 5.38-5.32 (m, 1H), 4.39-4.28 (m, 1H), 3.70- 3.62(m, 2H), 3.52-3.44 (m, 2H), 3.42 (s, 3H), 2.85 (tt, J = 7.3, 3.9 Hz,1H), 2.44 (s, 3H), 2.15-2.09 (m, 2H), 1.85-1.53 (m, 6H), 0.86-0.77 (m,2H), 0.66- 0.59 (m, 2H).

C81 [C₂₄H₃₀N₆O₂ + H]⁺ 435.2; 435.3 free base; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H),7.30 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.34 (quint, J = 6.6 Hz, 1H),3.82 (t, J = 5.6 Hz, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.85 (tt, J = 7.3,3.8 Hz, 1H), 2.44 (s, 3H), 2.18-2.07 (m, 2H), 1.86-1.51 (m, 6H), 0.85-0.77 (m, 2H), 0.66-0.59 (m, 2H).

C82 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base; 99.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.3, 1.5 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 4.12-4.20 (m, 2H), 3.94- 4.01(m, 2H), 3.80-3.88 (m, 1H), 3.49-3.58 (m, 1H), 3.43 (td, J = 11.7, 1.6Hz, 2H), 3.33-3.37 (m, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.80-2.90 (m, 1H),2.45 (s, 3H), 2.09-2.17 (m, 1H), 1.93-2.07 (m, 1H), 1.81-1.90 (m, 1H),1.61-1.79 (m, 4H), 1.38 (qd, J = 12.3, 4.4 Hz, 2H), 0.78-0.85 (m, 2H),0.60-0.66 (m, 2H).

C83 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base: 99.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 8.05 (s, 1H), 7.91 (dd, J = 8.3, 1.5 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 4.12-4.20 (m, 2H), 3.94- 4.01(m, 2H), 3.80-3.88 (m, 1H), 3.49-3.58 (m, 1H), 3.43 (td, J = 11.7, 1.6Hz, 2H), 3.33-3.37 (m, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.80-2.90 (m, 1H),2.45 (s, 3H), 2.09-2.17 (m, 1H), 1.93-2.07 (m, 1H), 1.81-1.90 (m, 1H),1.61-1.79 (m, 4H), 1.38 (qd, J = 12.3, 4.4 Hz, 2H), 0.78-0.85 (m, 2H),0.60-0.66 (m, 2H).

C84 [C₂₉H₃₇N₇O₃ + H]⁺ 532.3; 532.4 free base; 97.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.26 (s, 1H), 7.96-7.91 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H),5.60 (s, 1H), 3.97 (dd, J = 11.2, 3.4 Hz, 2H), 3.83-3.76 (m, 2H), 3.71(s, 4H), 3.70-3.66 (m, 2H), 3.43 (td, J = 11.8, 2.0 Hz, 2H), 3.29 (d, J= 7.0 Hz, 2H), 2.86 (tt, J = 7.3, 3.7 Hz, 1H), 2.45 (s, 3H), 2.17 (s,3H), 2.06- 1.93 (m, 1H), 1.76 (dd, J = 12.7, 1.6 Hz, 2H), 1.40 (qd, J =12.4, 4.4 Hz, 2H), 0.86-0.79 (m, 2H), 0.66-0.60 (m, 2H).

C85 [C₃₀H₃₄N₆O₄ + H]⁺ 543.3; 543.4 free base; 98.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.34 (s, 1H), 7.87 (s, 1H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H),7.36 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.92-6.78 (m, 3H),5.78 (s, 1H), 3.81 (s, 3H), 3.76-3.69 (m, 4H), 3.51 (s, 2H), 2.83 (tt, J= 7.4, 3.8 Hz, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.55 (br, s, 4H), 2.28 (s,3H), 0.84- 0.77 (m, 2H), 0.63-0.57 (m, 2H).

C86 [C₃₀H₃₄N₆O₅S + H]⁺ 591.2; 591.4 free base; 97.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.40-8.36 (m, 1H), 7.93-7.88 (m, 2H), 7.80-7.70 (m, 2H),7.69-7.62 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 3.76 (m, J =4.5 Hz, 4H), 3.60 (t, J = 6.4 Hz, 2H), 3.16 (s, 3H), 2.86-2.80 (m, 1H),2.78 (t, J = 6.3 Hz, 2H), 2.64-2.56 (m, 4H), 2.26 (s, 3H), 0.84-0.77 (m,2H), 0.63-0.57 (m, 2H).

C87 [C₂₈H₃₄N₆O₄ + H]⁺ 521.3; 521.4 free base; 98.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.25 (s, 1H), 7.98-7.90 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H),5.60 (s, 1H), 4.38-4.29 (m, 1H), 4.26-4.17 (m, 2H), 4.05-3.92 (m, 4H),3.76-3.59 (m, 3H), 3.44 (td, J = 11.8, 2.0 Hz, 2H), 3.31-3.28 (m, 2H),3.28-3.22 (m, 1H), 2.85 (tt, J = 7.4, 3.8 Hz, 1H), 2.45 (s, 3H), 2.08-1.94 (m, 1H), 1.81-1.73 (m, 2H), 1.47-1.34 (m, 2H), 0.86-0.78 (m, 2H),0.65-0.59 (m, 2H).

C88 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.5 free base; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.16 (s, 1H), 7.90 (s, 1H), 7.73 (dd, J = 8.2, 1.4 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 5.56-5.54 (m, 1H), 4.02-3.96 (m, 4H),3.81-3.76 (m, 3H), 3.50-3.41 (m, 2H), 3.35-3.30 (m, 2H), 3.25 (d, J =6.8 Hz, 2H), 2.90-2.82 (m, 1H), 2.44 (s, 3H), 2.42-2.38 (m, 1H),2.10-1.98 (m, 1H), 1.89-1.72 (m, 4H), 1.47-1.34 (m, 2H), 0.85- 0.79 (m,2H), 0.65-0.60 (m, 2H).

C89 [C₃₀H₄₀N₆O₄ + H]⁺ 549.3; 549.5 free base; 98.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 8.01 (s, 1H), 7.92-7.83 (m, 1H), 7.30 (d, J =8.0 Hz, 1H), 5.34 (s, 1H), 4.23-4.08 (m, 1H), 4.00-43.68 (m, 6H),3.46-3.22 (m, 4H), 3.05 (d, J = 7.0 Hz, 2H), 2.84 (tt, J = 7.3, 3.7 Hz,1H), 2.44 (s, 3H), 2.08- 1.96 (m, 1H), 1.90-1.69 (m, 3H), 1.67-1.42 (m,4H), 1.35-1.13 (m, 2H), 0.84-0.76 (m, 2H), 0.65- 0.57 (m, 2H).

C90 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.5 free base; 98.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.92-7.99 (m, 2H), 7.29 (d, J = 8.5 Hz, 1H),5.36 (s, 1H), 4.62 (br. s., 1H), 4.17 (dd, J = 9.3, 5.3 Hz, 1H), 4.06-3.98 (m, 2H), 3.95 (dd, J = 11.2, 3.4 Hz, 2H), 3.85- 3.73 (m, 3H), 3.57(dq, J = 9.3, 7.0 Hz, 1H), 3.40 (td, J = 11.8, 2.0 Hz, 2H), 3.18 (d, J =7.0 Hz, 2H), 2.90-2.81 (m, 1H), 2.45 (s, 3H), 2.01-1.88 (m, 1H),1.76-1.65 (m, 2H), 1.35 (qd, J = 12.5, 4.5 Hz, 2H), 1.19 (t, J = 7.0 Hz,3H), 0.87-0.77 (m, 2H), 0.66- 0.60 (m, 2H).

C91 [C₃₃H₃₉N₇O₄ + H]⁺ 598.3; 598.4 free base; 98.5% at 254 nm (400 MHz,CDCl₃) δ ppm 8.27 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H),7.37-7.30 (m, 1H), 7.27-7.24 (m, 1H), 6.87-6.78 (m, 4H), 5.62 (s, 1H),3.88-3.82 (m, 4H), 3.82-3.75 (m, 4H), 3.48-3.41 (m, 2H), 3.22-3.15 (m,4H), 2.93-2.85 (s, 1H), 2.78 (t, J = 5.9 Hz, 2H), 2.56 (br. s., 4H),2.38 (s, 3H), 1.59-1.55 (m, 1H), 0.91-0.83 (m, 2H), 0.64-0.56 (m, 2H).

C92 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.4 free base; 99.1% at 254 nm (400 MHz,CD₃OD) δ ppm 8.17 (s, 1H), 8.09 (s, 1H), 7.90 (dd, J = 8.0, 1.3 Hz, 1H),7.30 (d, J = 8.0 Hz, 1H), 5.45 (s, 1H), 4.39-4.29 (m, 1H), 3.79- 3.67(m, 4H), 3.65 (s, 2H), 3.37 (s, 2H), 2.85 (tt, J = 7.3, 3.8 Hz, 1H),2.44 (s, 3H), 2.19-2.09 (m, 2H), 1.86-1.74 (m, 2H), 1.74-1.53 (m, 8H),0.86- 0.78 (m, 2H), 0.67-0.59 (m, 2H).

C93 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3; 535.4 free base; 98.7% at 254 nm NMR (400MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.10 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz,1H), 7.31 (d, J = 8.3 Hz, 1H), 5.47 (s, 1H), 4.25-4.14 (m, 1H), 4.08-4.00 (m, 2H), 3.79-3.69 (m, 4H), 3.68-3.65 (m, 2H), 3.62 (td, J = 11.7,2.3 Hz, 2H), 3.39 (s, 2H), 2.89-2.82 (m, 1H), 2.45 (s, 3H), 2.19-2.10(m, 2H), 1.69-1.56 (m, 6H), 0.85-0.78 (m, 2H), 0.66-0.61 (m, 2H).

C94 [C₂₈H₃₆N₆O₄ + H]⁺ 521.3; 521.4 free base; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 8.10 (s, 1H), 7.88-7.83 (m, 1H), 7.31 (d, J =8.0 Hz, 1H), 5.42 (s, 1H), 4.25-4.13 (m, 1H), 4.08-3.99 (m, 2H),3.86-3.72 (m, 4H), 3.61 (td, J = 11.6, 1.9 Hz, 2H), 3.35-3.28 (m, 2H),2.91-2.80 (m, 1H), 2.45 (s, 3H), 2.19-2.09 (m, 2H), 1.84-1.73 (m, 2H),1.69- 1.55 (m, 4H), 0.86-0.78 (m, 2H), 0.67-0.60 (m, 2H).

C95 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.4 free base; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, H), 8.09 (s, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H),7.30 (d, J = 8.0 Hz, 1H), 5.41 (s, 1H), 4.34 (quin, J = 6.7 Hz, 1H),3.87-3.72 (m, 4H), 3.35-3.27 (m, 2H), 2.91- 2.81 (m, 1H), 2.44 (s, 3H),2.20-2.08 (m, 2H), 1.87-1.51 (m, 10H), 0.86-0.77 (m, 2H), 0.67- 0.60 (m,2H).

C96 [C₃₁H₃₇N₇O₃ + H]⁺ 556.3; 556.5 free base; 95.2% at 254 nm (400 MHz,CD₃OD) δ ppm 8.35 (s, 1H), 7.90 (s, 1H), 7.71-7.65 (m, 1H), 7.28 (t, J =8.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.72-6.63 (m, 2H), 6.58 (dd, J =7.8, 1.8 Hz, 1H), 5.75 (s, 1H), 3.77-3.70 (m, 4H), 3.51 (t, J = 6.3 Hz,2H), 2.96 (s, 6H), 2.84 (tt, J = 7.4, 3.7 Hz, 1H), 2.71 (t, J = 6.4 Hz,2H), 2.55 (br. s., 4H), 2.29 (s, 3H), 0.85-0.76 (m, 2H), 0.64-0.58 (m,2H).

C97 [C₂₉H₃₁ClN₆O₃ + H]⁺ 547.2; 547.3 free base; 95.3% at 254 nm (400MHz, CD₃OD) δ ppm 8.35 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 7.0 Hz, 1H),7.40-7.49 (m, 1H), 7.37 (t, J = 2.1 Hz, 1H), 7.34-7.27 (m, 1H), 7.22 (d,J = 8.0 Hz, 2H), 5.86 (s, 1H), 3.75 (t, J = 4.5 Hz, 4H), 3.57 (t, J =6.4 Hz, 2H), 2.88-2.80 (m, 1H), 2.77 (t, J = 6.4 Hz, 2H), 2.59 (br. s.,4H), 2.29 (s, 3H), 0.77-0.83 (s, 2H), 0.57-0.64 (m, 2H).

C98 [C₂₈H₃₀N₆O₄ + H]⁺ 515.2; 515.3 free base; 97.7% at 254 nm NMR (400MHz, CD₃OD) δ ppm 8.55 (d, J = 2.8 Hz, 1H), 8.48 (dd, J = 4.8, 1.3 Hz,1H), 8.36 (s, 1H), 7.86-7.80 (m, 1H), 7.73 (s, 1H), 7.62-7.54 (m, 2H),7.19 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 3.87- 3.74 (m, 4H), 3.47 (s,2H), 2.89-2.77 (m, 1H), 2.26 (s, 3H), 1.87-1.75 (m, 2H), 1.72-1.61 (m,2H), 0.84-0.76 (m, 2H), 0.65-0.56 (m, 2H).

C99 [C₂₉H₃₂N₆O₄ + H]⁺ 529.3; 529.4 free base; 97.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.57 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 4.8, 1.3 Hz, 1H),8.36 (s, 1H), 7.87-7.83 (m, 1H), 7.75 (s, 1H), 7.62-7.57 (m, 2H), 7.19(d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 3.82-3.68 (m, 6H), 3.54 (s, 2H),2.87-2.79 (m, 1H), 2.26 (s, 3H), 1.63-1.66 (m, 4H), 0.82-0.78 (m, 2H),0.63- 0.58 (m, 2H).

C100 [C₂₆H₂₆N₆O₃ + H]⁺ 471.2 471.1; free base; 91.9% at 254 nm (400 MHz,CDCl₃ + drops of CD₃OD) δ ppm 8.58 (br. s., 1H), 8.49 (br. s., 1H), 8.22(s, 1H), 7.73- 7.61 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.46-7.39 (m,1H), 7.21 (d, J = 8.8 Hz, 1H), 5.76 (s, 1H), 4.93 (t, J = 6.4 Hz, 2H),4.50 (t, J = 5.8 Hz, 2H), 3.76 (d, J = 6.5 Hz, 2H), 3.41 (d, J = 11.5Hz, 1H), 2.85 (br. s., 1H), 2.31 (br. s., 3H), 0.94-0.82 (m, 2H), 0.62-0.53 (m, 2H);

C101 [C₂₈H₃₂N₆O₄ + H]⁺ 493.2; 493.3 free base; 94% at 254 nm (400 MHz,CDCl₃) δ ppm 8.24 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.38(d, J = 8.0 Hz, 1H), 6.79 (t, J = 4.8 Hz, 1H), 5.95 (br. s., 1H), 5.74(quint, J = 5.9 Hz, 1H), 5.50 (s, 1H), 5.07 (t, J = 7.2 Hz, 2H), 4.83(dd, J = 7.8, 5.5 Hz, 2H), 3.82- 3.73 (m, 4H), 3.45-3.38 (m, 2H),2.97-2.87 (m, 1H), 2.76 (t, J = 6.0 Hz, 2H), 2.59-2.50 (s, 7H),0.94-0.85 (m, 2H), 0.63 (m, 2H);

C102 [C₂₆H₃₂N₆O₃ + H]⁺ 477.3; 477.3 free base; 93% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.32(d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 5.14 (m, 1H), 5.07-5.00 (m, 2H), 4.68(t, J = 6.4 Hz, 2H), 3.98 (dd, J = 11.3, 3.3 Hz, 2H), 3.43 (td, J =11.7, 1.9 Hz, 2H), 3.23 (d, J = 7.0 Hz, 2H), 2.86 (tt, J= 7.3, 3.8 Hz,1H), 2.47 (s, 3H), 2.06-1.95 (m, 1H), 1.75 (d, J = 12.8 Hz, 2H),1.46-1.32 (m, 2H), 0.85-0.76 (m, 2H), 0.66-0.60 (m, 2H).

C103 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.6; HCl salt; 98.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 7.47 (s, 1H), 7.45-7.39 (m, 2H), 5.54 (s,1H), 3.98 (dd, J = 11.0, 3.0 Hz, 2H), 3.50-3.43 (m, 4H), 2.92-2.87 (m,1H), 2.48 (s, 3H), 2.08 (s, br, 1H), 1.80-1.73 (m, 2H), 1.50-1.37 (m,2H), 0.87-0.81 (m, 2H), 0.71- 0.63 (m, 4H), 0.43-0.37 (m, 2H).

C104 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3 TFA salt; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 7.55-7.37 (m, 3H), 5.67 (s, 1H), 3.98 (dd, J= 11.6, 3.6 Hz, 2H), 3.87 (s, br, 1H), 3.69-3.57 (m, 2H), 3.47-3.33 (m,7H), 2.91-2.85 (m, 1H), 2.46 (s, 3H), 2.12-1.98 (m, 2H), 1.77-1.70 (m,2H), 1.48-1.35 (m, 2H), 1.10-1.04 (m, 6H), 0.85-0.80 (m, 2H), 0.66-0.61(m, 2H),

C105 [C₂₈H₂₉ClN₆O₃ + H]⁺ 533.2; 533.2 TFA salt; 99.1% at 254 nm (400MHz, CD₃OD) δ ppm 8.27 (s, 1H), 7.96 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H),7.45 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 4H), 5.89 (s, 1H), 4.15-3.80 (m,6H), 3.80-3.50 (m, 4H), 3.35-3.15 (m, 2H), 2.89- 2.82 (m, 1H), 0.84-0.78(m, 2H), 0.67-0.60 (m, 2H).

C106 [C₃₁H₃₆N₆O₃ + H]⁺ 541.3; 541.3 TFA salt; 96.1% at 254 nm (400 MHz,CD₃OD) δ ppm 8.40 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48(t, J = 7.6 Hz, 2H), 7.33-7.27 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 6.18(s, 1H), 4.07 (s, 2H), 4.06-3.98 (m, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.32(quint, J = 1.6 Hz, 1H), 2.94 (s, 6H), 2.87-2.79 (m, 1H), 2.25 (s, 3H),2.27- 2.01 (m, 2H), 0.83-0.77 (m, 2H), 0.63-0.58 (m, 2H).

C107 [C₂₇H₃₄N₆O₄ + H]⁺ 507.3; 507.2 TFA salt; 98.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.48 (s, 1H), 7.46-7.37 (m, 2H), 5.62 (s,1H), 4.55-4.50 (m, 1H), 4.41 (q, J = 6.0 Hz, 1H), 4.21 (dd, J = 8.4, 7.2Hz, 1H), 4.07 (dd, J = 10.0, 4.8 Hz, 1H), 3.99 (dd, J = 11.4, 7.4 Hz,2H), 3.83 (dd, J = 9.8, 2.6 Hz, 1H), 3.73-3.67 (m, 1H), 3.50-3.40 (m,4H), 2.92-2.86 (m, 1H), 2.46 (s, 3H), 2.13-2.01 (m, 1H), 1.78-1.72 (m,2H), 1.50-1.38 (m, 2H), 0.86-0.81 (m, 2H), 0.67-0.61 (m, 2H).

C108 [C₂₆H₃₄N₆O₃ + H]⁺ 479.3; 479.2 TFA salt; 98.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.47 (s, 1H), 7.46-7.40 (m, 2H), 5.73 (s,1H), 4.05-3.98 (m, 1H), 3.95-3.83 (m, 1H), 3.77-3.68 (m, 4H), 3.42 (s,3H), 2.92-2.87 (m, 1H), 2.47 (s, 3H), 1.90-1.67 (m, 6H), 1.60-1.43 (m,2H), 0.87-0.81 (m, 2H), 0.66- 0.62 (m, 2H).

C109 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.2 TFA salt; 99.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.17 (s, 1H), 7.45 (s, 1H), 7.43-7.38 (m, 2H), 5.41 (s,1H), 4.30 (quint, J = 7.90, 1H), 3.98 (dd, J = 11.6. 3.2 Hz, 2H), 3.49-3.40 (m, 4H), 2.92-2.87 (m, 1H), 2.46 (s, 3H), 2.17-2.00 (m, 3H),1.96-1.87 (m, 2H), 1.78-1.72 (m, 2H), 1.49-1.38 (m, 2H), 0.86-0.81 (m,2H), 0.67-0.62 (m, 2H).

C110 [C₂₆H₃₄N₆O₄ + H]⁺ 495.3; 495.3 HCl salt; 97.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.30 (m, 3H), 5.74 (s, 1H), 4.10-3.65(m, 7H), 3.55-3.25 (m, 4H), 2.93-2.83 (m, 1H), 2.46 (s, 3H), 2.20-2.04(m, 1H), 1.85-1.65 (m, 2H), 1.55-1.30 (m, 2H), 0.85-0.75 (m, 2H),0.70-0.58 (m, 2H).

C111 [C₂₈H₃₇N₇O₃ + H]⁺ 520.3; 520.3 HCl salt; 98.7% at 254 nm (400 MHz,CD₃OD) δ ppm 8.22 (s, 1H), 7.60-7.30 (m, 3H), 5.46 (s, 1H), 4.40-3.85(m, 3H), 3.75-3.25 (m, 4H), 2.92-2.84 (m, 1H), 2.46 (s, 3H), 2.40-2.25(m, 1H), 2.20-1.98 (m, 1H), 1.85-1.65 (m, 2H), 1.60-1.35 (m, 2H),1.25-1.00 (m, 6H), 0.85-0.75 (m, 2H), 0.70-0.58 (m, 2H).

C112 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3; 517.3 HCl salt; 97.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.15 (s, 1H), 7.52-7.33 (m, 3H), 4.70-4.55 (m, 2H),4.05-3.65 (m, 6H), 3.55-3.47 (m, 4H), 2.92-2.82 (m, 1H), 2.55 (s, 3H),2.30-2.00 (m, 5H), 1.85-1.73 (m, 2H), 1.55-1.37 (m, 2H). 0.86-0.80 (m,2H), 0.65-0.60 (m, 2H).

C113 C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3 HCl salt; 98.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 7.53-7.35 (m, 3H), 3.98 (s, 2H), 3.65-3.30(m, 8H), 2.92-2.84 (m, 1H), 2.47 (s, 3H), 2.20-2.05 (m, 1H), 1.85-1.67(m, 2H), 1.52-1.38 (m, 2H), 0.85-0.78 (m, 2H), 0.72-0.52 (m, 6H).

C114 [C₂₉H₃₉N₇O₃ + H]⁺ 534.3; 534.6 free base; 99.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 7.98-7.94 (m, 2H), 7.30 (d, J = 1.6 Hz, 1H),5.37 (s, 1H), 4.00-3.96 (m, 2H), 3.73-3.71 (m, 4H), 3.66 (t, J = 6.8 Hz,2H), 3.43 (t, J = 9.6 Hz, 2H), 3.24 (d, J = 6.8 Hz, 2H), 2.87-2.84 (m,1H), 2.71-2.68 (m, 2H), 2.59 (s, 4H), 2.45 (s, 3H), 2.03-2.00 (m, 1H),1.77- 1.75 (m, 2H), 1.45-1.35 (m, 2H), 0.84-0.79 (m, 2H), 0.64-0.60 (m,2H).

C115 [C₃₁H₄₀N₆O₄ + H]⁺ 562.3; 562.3; free base; 96.8% at 254 nM (400MHz, CD₃OD) δ ppm 8.31 (s, 1H), 8.00 (s, 1H), 7.86-7.84 (m, 1H), 7.32(d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.22-5.21 (m, 1H), 4.72-4.67 (m, 2H),4.63-4.59 (m, 2H), 3.97-3.94 (m, 2H), 3.55-3.50 (m, 1H), 3.44-3.41 (m,2H), 3.27-3.23 (m, 2H), 2.88-2.84 (m, 1H), 2.73-2.63 (m, 2H), 2.44 (s,3H), 2.26-2.17 (m, 9H), 1.74-1.71 (m, 2H), 1.42-1.32 (m, 2H), 0.84-0.79(m, 2H), 0.65-0.61 (m, 2H).

C116 [C₃₀H₃₈N₆O₄ + H]⁺ 547.3; 547.6; TFA salt; 96.7% at 254 nM (400 MHz,CD₃OD) δ ppm 8.36 (s, 1H), 7.93-7.88 (m, 2 H), 7.34 (d, J = 8.0 Hz, 1H),5.87 (s, 1H), 5.67 (s, 1H), 4.97-4.92 (m, 3H), 4.77-4.74 (m, 2H),4.63-4.59 (m, 1H), 3.96-3.65 (m, 7H), 3.56-3.45 (m, 3H), 2.89-2.84 (m,1H), 2.68-2.66 (m, 1H), 2.46 (s, 3H), 2.06-1.98 (m, 1H), 1.76-1.73 (m,2H), 1.45-1.35 (m, 2H), 0.85-0.80 (m, 2H), 0.65-0.61 (m, 2H).

C117 [C₂₉H₃₈N₆O₄ + H]⁺ 535.3 535.3 TFA salt; 97.6% at 254 nM (400 MHz,CD₃OD) δ ppm 8.35 (s, 1H), 7.93-7.89 (m, 2H), 7.34 (d, J = 8.0 Hz. 1H),5.69 (s, 1H), 4.91-4.88 (m, 2H), 4.86 (t, J = 4.8 Hz, 2H), 4.03- 3.96(m, 4H), 3.79-3.76 (m, 2H), 3.72-3.65 (m, 4H), 3.45-3.40 (m, 2H),3.30-3.38 (m, 2H), 2.89- 2.84 (m, 1H), 2.46 (s, 3H), 2.06-1.99 (m, 1H),1.76-1.73 (m, 2H), 1.45-1.35 (m, 2H), 0.85-0.80 (m, 2H), 0.65-0.61 (m,2H).

C118 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 98.9% at 254 nM (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.47 (s, 1H), 7.43 (m, 2H), 5.69 (s, 1H),4.01-3.95 (m, 4H), 3.47-3.41 (m, 4H), 2.91-2.85 (m, 1H), 2.47 (s, 3H),2.10-2.04 (m, 1H), 1.82-1.69 (m, 8H), 1.56-1.37 (m, 4H), 0.86-0.81 (m,2H), 0.65-0.61 (m, 2H).

C119 [C₂₈H₃₉N₇O₃ + H]⁺ 522.3; 522.3; free base; 95% at 254 nM (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.31(d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 4.04-3.97 (m, 2H), 3.74 (t, J = 4.8Hz, 4H), 3.46-3.42 (m, 2H), 2.88-2.82 (m, 1H), 2.74-2.70 (m, 2H), 2.56(br.s, 4H), 2.45 (s, 3H), 1.81-1.73 (m, 1H), 1.7-1.61 (m, 1H), 1.22 (d,J = 6.4 Hz, 3H), 1.03 (t, J = 8.0 Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60(m, 2H).

C120 [C₃₀H₃₉N₇O₃ + H]⁺ 547.3; 547.3; di-TFA salt; 98.7% at 254 nM (400MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.81-7.65 (m, 2H), 7.35 (d, J = 7.6 Hz,1H), 4.93-4.85 (m, 2H), 4.81-4.75 (m, 1H), 4.74-4.70 (m, 2H), 4.60- 4.54(m, 1H), 4.00-3.96 (m, 3H), 3.79-3.70 (m, 3H), 3.53-3.40 (m, 3H),3.36-3.31 (m, 2H), 2.87- 2.84 (m, 1H), 2.69-2.60 (m, 1H), 2.46 (s, 3H),2.32-2.24 (m, 1H), 2.08-1.99 (m, 1H), 1.77-1.74 (m, 2H), 1.46-1.35 (m,2H), 0.85-0.80 (m, 2H), 0.64-0.61 (m, 2H).

C121 [C₂₈H₃₈N₆O₃ + H]⁺ 507.3; 507.3; TFA salt: 99.5% at 254 nM (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.70 (s,1H), 4.00-3.97 (m, 2H), 3.85-3.67 (m, 3H), 3.46-3.41 (m, 4H), 2.91- 2.85(m, 1H), 2.47 (s, 3H), 2.11-2.02 (m, 2H), 1.76-1.73 (m, 2H), 1.47-1.77(m, 2H), 1.08 (t, J = 6.8 Hz, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C122 [C₃₁H₄₁N₇O₃ + H]⁺ 560.3; 560.3; di-TFA salt; 99.9% at 254 nM (400MHz, CD₃OD) δ ppm 8.21 (s, 1H), 7.61-7.58 (m, 2H), 7.38 (d, J = 8.0 Hz,1H), 4.90-4.83 (m, 5H), 4.48-4.45 (m, 1H), 4.19-4.15 (m, 1H), 4.00- 3.96(m, 2H), 3.65-3.43 (m, 6H), 3.14-3.06 (m, 2H), 2.90-2.86 (m, 1H),2.45-2.36 (m, 5H), 2.10- 1.92 (m, 3H), 1.77-1.74 (m, 2H), 1.47-1.37 (m,2H), 0.85-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C123 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; TFA salt; 97.1% at 254 nM (400 MHz,CD₃OD) δ ppm 8.22 (s, 1H), 7.50 (s, 1H), 7.46-7.40 (m, 2H), 5.58 (s,1H), 4.10-4.05 (m, 1H), 4.00-3.97 (m, 2H), 3.91-3.86 (m, 1H), 3.46- 3.38(m, 4 H), 2.87-2.85 (m, 1H), 2.46 (s, 3H), 2.31-2.24 (m, 1H), 2.12-2.06(m, 2H), 1.94-1.69 (m, 6H), 1.46-1.36 (m, 2H), 0.86-0.81 (m, 2H),0.65-0.61 (m,2H).

C124 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 99.5% at 254 nM (400 MHz,CD₃OD) δ ppm 8.24 (s, 1H), 7.51 (s, 1H), 7.46-7.41 (m, 2H), 5.64 (s, 1H), 3.98 (dd, J = 11.2, 3.2 Hz, 2H), 3.53 (m, 2H), 3.46-3.38 (m, 4H),2.90-2.85 (m, 1H), 2.47 (s, 3H), 2.12-2.03 (m, 3H), 1.81-1.73 (m, 4H),1.47-1.34 (m, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C125 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3; TFA salt; 99.1% at 254 nM (400 MHz,CD₃OD) δ ppm 8.24 (s, 1H), 7.52 (s, 1H), 7.46-7.42 (m, 2H), 5.64 (s,1H), 4.00-3.97 (m, 2H), 3.53 (m, 2H), 3.46-3.35 (m, 4H), 2.90-2.85 (m,1H), 2.47 (s, 3H), 2.12-2.03 (m, 3H), 1.80-1.73 (m, 4H), 1.54-1.34 (m,6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m, 2H).

C126 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; free base; 97.6% at 254 nM (400MHz, CD₃OD) δ ppm 8.20 (s, 1H), 7.47 (s, 1H), 7.42 (br. s, 2H), 5.60 (s,1H), 4.30-4.27 (m, 1H), 4.07-4.02 (m, 1H), 4.00-3.97 (m, 2H), 3.47- 3.41(m, 4H), 2.89-2.85 (m, 1H), 2.47 (s, 3H), 2.22-2.18 (m, 1H), 2.11-1.91(m, 3H), 1.82-1.69 (m, 5H), 1.48-1.38 (m, 2H), 0.86-0.81 (m, 2H),0.65-0.61 (m, 2H).

C127 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3; free base; 98.9% at 254 nM (400MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.97 (s, 1H), 7.86 (dd, J = 8.0 Hz, 1.6Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.46 (s, 1H), 4.08 (br. s, 1H), 3.98(dd, J = 11.6, 3.6 Hz, 2H), 3.47-3.43 (m, 2H), 3.25 (d, J = 7.2 Hz, 2H),2.85-2.82 (m, 1H), 2.46 (s, 3H), 2.05-2.00 (m, 1H), 1.99-1.86 (m, 1H),1.78-1.75 (m, 2H), 1.52-1.34 (m, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.01(t, J = 7.2 Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C128 [C₂₉H₄₂N₆O₃ + H]⁺ 523.3; 523.3; free base; 98.7% at 254 nM (400MHz, CD₃OD) δ ppm 8.18 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz,1H), 7.31 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 3.40-3.34 (m, 3H), 3.30 (s,3H), 2.88-2.83 (m, 1H), 2.47 (s, 3H), 2.31-2.25 (m, 1H), 1.32 (s, 9H),1.26 (s, 3H), 1.05 (t, J = 6.4 Hz, 6H), 0.84-0.79 (m, 2H), 0.65-0.61 (m,2H).

C129 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.3; TFA salt; 97.1% at 254 nM (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.49 (s, 1H), 7.46-7.41 (m, 2H), 5.72 (s,1H), 4.31-4.28 (m, 1H), 4.05-3.00 (m, 1H), 3.61-3.53 (m, 2H), 3.29 (s,3H), 2.91-2.85 (m, 1H), 2.47 (s, 3H), 2.23- 2.05 (m, 1H), 2.03-1.93 (m,2H), 1.82-1.68 (m, 3H), 1.31 (s, 6H), 0.86-0.81 (m, 2H), 0.65-0.61 (m,2H).

C130 [C₂₉H₄₀N₆O₃ + H]⁺ 521.3; 521.3; HCl salt; 98.2% at 254 nM (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.48 (s, 1H), 7.43 (s, 2H), 5.67 (s, 1H),3.99-3.92 (m, 3H), 3.85-3.74 (m, 1H), 3.69-3.58 (m, 1H), 3.50-3.40 (m,4H), 2.90-2.85 (m, 1H), 2.47 (s, 3H), 2.13-2.03 (m, 1H), 1.77-1.73 (m,3H), 1.58-1.38 (m, 4H), 1.03- 0.98 (m, 6H), 0.85-0.81 (m, 2H), 0.65-0.61(m, 2H).

C131 [C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 533.3; free base; 96.7% at 254 nM (400MHz, CD₃OD) δ ▭ ppm 8.13 (s, 1H), 7.78- 7.74 (m, 2H), 7.31 (d, J = 8.0Hz, 1H), 5.58 (s, 1H), 4.49 (br, s, 1H), 3.97 (dd, J = 10.8, 2.8 Hz,2H), 3.46-3.43 (m, 2H), 3.43-3.40 (m, 2H), 3.28- 3.21 (m, 2H), 2.87-2.82(m, 1H), 2.44 (s, 3H), 2.04-2.00 (m, 1H), 1.98-1.80 (m, 2H), 1.77-1.64(m, 6H), 1.46-1.33 (m, 4H), 1.28-1.22 (m, 1H), 0.84-0.79 (m, 2H).0.64-0.60 (m, 2H).

C132 [C₂₉H₃₆N₈O₂ + H]⁺ 529.3; 529.2; free base; 96.4% at 254 nM (400MHz, CD₃OD) δ ppm 8.19 (s, 1H), 8.05 (s, 1H), 7.83 (dd, J = 8.0, 1.2 Hz,1H), 7.71 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.00 (s, 1H),5.34 (s, 1H), 4.21-4.14 (m, 4H), ), 3.40-3.29 (m, 2H), 2.88-2.83 (m,1H), 2.45 (s, 3H), 2.24-2.17 (m, 2H), 1.87-1.64 (m, 6H), 1.49-1.47 (m,2H), 0.84-0.79 (m, 2H), 0.65-0.61 (m, 2H).

C133 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.4; free base; 99.2% at 254 nM (400MHz, CD₃OD) δ ppm 8.38 (br, s, 1H), 8.17 (s, 1H), 7.98 (s, 1H),7.89-7.87 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.45 (s, 1H), 4.01-3.91 (m,3H), 3.88- 3.84 (m, 1H), 3.80-3.68 (m, 1H), 3.68-3.64 (m, 1H), 2.87-2.83(m, 1H), 2.73-2.70 (m, 1H), 2.45 (s, 3H), 2.16-2.12 (m, 1H), 1.79-1.73(m, 2H), 1.69-1.63 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.03 (t, J = 7.6Hz, 3H), 0.84-0.79 (m, 2H), 0.64-0.60 (m, 2H).

C134 [C₂₇H₃₆N₆O₃ + H]⁺ 493.3; 493.4; free base; 95.5% at 254 nM (400MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.98 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz,1H), 7.31 (d, J = 8.4 Hz, 1H), 5.45 (s, 1H), 4.85-4.95 (m, 2H), 4.00-3.89 (m, 3H), 3.87-3.85 (m, 1H), 3.80-3.75 (m, 1H), 3.68-3.65 (m, 1H),2.87-2.83 (m, 1H), 2.73-2.71 (m, 1H), 2.45 (s, 3H), 2.17-2.13 (m, 1H),1.80-1.74 (m, 2H), 1.69-1.65 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.03 (t,J = 7.6 Hz, 3H), 0.84-0.79 (m, 2H), 064-0.60 (m, 2H).

C135 [C₂₈H₃₀N₆O₃ + H]⁺ 499.2; 499.3; free base; 98.9% at 254 nM (400MHz, CD₃OD) δ ppm 8.55 (dd, J = 2.8, 0.4 Hz, 1H), 8.47 (dd, J = 4.8, 1.6Hz, 1H), 8.33 (s, 1H), 7.83-7.80 (m, 1H), 7.72 (s, 1H), 7.58-7.55 (m,2H), 7.18 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 3.49 (d, J = 1.6 Hz, 2H),2.87-2.78 (m, 2H), 2.28- 2.23 (m, 5H), 1.97-1.92 (m, 2H), 1.36 (s, 3H),0.82-0.77 (m, 2H), 0.62-0.58 (m, 2H).

C136 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.3; TFA salt; 98.2% at 254 nm (400 MHz,CDCl₃) δ ppm 9.35 (br, s, 2H), 7.91 (s, 1H), 7.36-7.28 (m, 1H),7.25-7.17 (m, 2H), 7.13 (t, J = 5.6 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H),5.13 (s, 1H), 4.21 (br, s, 1H), 4.11-3.97 (m, 4H), 3.94-3.86 (m, 1H),3.80 (dd, J = 9.5, 3.5 Hz, 1H), 3.44 (t, J = 11.2 Hz, 2H), 3.37 (t, J =6.4 Hz, 2H), 2.97-2.85 (m, 1H), 2.44-2.29 (m, 4H), 2.18-1.97 (m, 2H),1.76 (d, J = 12.5 Hz, 2H), 1.56-1.37 (m, 2H), 0.95- 0.78 (m, 2H),0.71-0.57 (in, 2H).

C137 [C₂₇H₃₄N₆O₄ + H]⁺ 507.3; 507.3; TFA salt; 98.8% at 254 nm (400 MHz,CDCl₃) δ ppm 9.33-8.18 (m, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.64 (d, J =8.0 Hz, 1H), 7.29 (s, 1H), 6.94 (br, s, 1H), 6.61 (d, J = 2.8 Hz, 1H),5.46 (br, s, 1H), 5.33 (s, 1H), 4.06-3.84 (m, 7H), 3.83-3.52 (m, 5H),3.37 (br, s, 2H), 3.15-2.73 (m, 3H), 2.43 (s, 3H), 2.33-2.21 (m, 1H),2.21-2.09 (m, 1H), 0.97-0.80 (m, 2H), 0.72-0.53 (m, 2H).

C138 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 419.3; TFA salt; 99.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.58-7.44 (m, 2H), 7.43-7.35 (m, 1H),4.56-4.44 (m, 1H), 4.08-3.94 (m, 4H), 3.93-3.81 (m, 2H), 3.51-3.38 (m,4H), 2.94-2.82 (m, 1H), 2.46 (s, 3H), 2.44-2.37 (m, 1H), 2.15-1.97 (m,2H), 1.76 (d, J = 12.8 Hz, 2H), 1.43 (qd, J = 12.4, 4.4 Hz, 2H),0.88-0.78 (m, 2H), 0.69-0.58 (m, 2H).

C139 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; TFA salt; 99.2% at 254 nm (400 MHz,CDCl₃) δ ppm 8.95-9.65 (m, 2H), 7.94 (br, s, 1H), 7.44-7.18 (m, 2H),6.89 (br, s, 2H), 6.59-6.22 (m, 1H), 5.76 (br, s, 1H), 4.03 (br, s, 2H),3.67 (br, s, 2H), 3.51-3.18 (m, 4H), 2.99-2.81 (m, 1H), 2.42 (br, s,3H), 2.16-1.88 (m, 1H), 1.82-1.62 (m, 2H), 1.59-1.27 (m, 2H), 1.01 (d, J= 5.0 Hz, 4H), 0.91-0.78 (m, 2H), 0.64 (br, s, 2H).

C140 [C₂₆H₃₄N₆O₄S + H]⁺ 527.2; 527.2; HCl salt: 99.9% at 254 nm (400MHz, DMSO-d₆) δ ppm 8.42 (br, s, 1 H), 8.22 (br, s, 1 H), 8.08-7.56 (m,3H), 7.39-7.24 (m, 2H), 7.18 (s, 1H), 7.04 (s, 1H), 5.44 (br, s, 2H),4.03 (br, s, 1H), 3.96-3.84 (m, 2H), 3.25-3.17 (m, 2H), 2.99 (s, 3H),2.87-2.74 (m, 1H), 2.37 (s, 3H), 2.13-1.89 (m, 4H), 1.60-1.40 (m, 2H),0.73-0.61 (m, 2H), 0.59-0.45 (m, 2H).

C141 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3; 517.3; free base; 97.8% at 254 nm (400MHz, CDCl₃) δ ppm 8.13 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H),7.35 (d, J = 8.0 Hz, 1H), 6.14 (t, J = 6.0 Hz, 1H), 5.93 (d, J = 2.5 Hz,1H), 5.06 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.82 (s, 2H), 4.67 (s, 2H),4.29-4.16 (m, 1H), 4.03 (dd, J = 11.8, 3.3 Hz, 2H), 3.41 (td, J = 11.9,1.9 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.96-2.79 (m, 3H), 2.53 (s, 3H),2.20-2.09 (m, 2H), 2.01-1.88 (m, 1H), 1.75 (d, J = 11.0 Hz, 2H),1.50-1.35 (m, 2H), 0.93-0.84 (m, 2H), 0.66-0.58 (m, 2H).

C142 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 98.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.14 (s, 1H), 7.52-7.38 (m, 3H), 4.64 (br, s, 1H), 3.99(dd, J = 11.3, 3.8 Hz, 2H), 3.84 (d, J = 7.5 Hz, 3H), 3.65 (d, J = 10.8Hz, 1H), 3.53-3.39 (m, 4H), 2.94-2.83 (m, 1H), 2.47 (s, 3H), 2.33-2.01(m, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.53-1.36 (m, 2H), 0.89-0.79 (m,2H), 0.72-0.59 (m, 2H).

C143 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 98.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.14 (s, 1H), 7.52-7.38 (m, 3H), 4.64 (br, s, 1H), 3.99(dd, J = 11.3, 3.8 Hz, 2H), 3.84 (d, J = 7.5 Hz, 3H), 3.65 (d, J = 10.8Hz, 1H), 3.53-3.39 (m, 4H), 2.94-2.83 (m, 1H), 2.47 (s, 3H), 2.33-2.01(m, 3H), 1.77 (d, J = 12.3 Hz, 2H), 1.53-1.36 (m, 2H), 0.89-0.79 (m,2H), 0.72-0.59 (m, 2H).

C144 [C₂₇H₂₈N₆O₃ + H]⁺ 485.2; 485.3; HCl salt; 98.8% at 254 nm (400 MHz,CD₃OD) δ ppm 9.13 (d, J = 2.3 Hz, 1H), 8.86 (d, J = 5.8 Hz, 1H),8.77-8.69 (m, 1H), 8.40 (s, 1H), 8.26 (dd, 8.8, 5.8 Hz, 1H), 7.67 (s,1H), 7.59 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H),4.53-4.39 (m, 1H), 3.57 (d, J = 8.0 Hz, 2H), 2.89-2.79 (m, 1H),2.76-2.61 (m, 1H), 2.30 (s, 3H), 2.29-2.21 (m, 2H), 2.21-2.08 (m, 2H),0.85-0.78 (m, 2H), 0.65-0.58 (m, 2H).

C145 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3; 491.2; HCl salt; 97.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 7.52-7.34 (m, 3H), 4.51-4.37 (m, 1H),4.11-3.91 (m, 3H), 3.73-3.53 (m, 4H), 2.94-2.82 (m, 1H), 2.76-2.59 (m,1H), 2.48 (s, 3H), 2.30-2.20 (m, 2H), 2.19-2.00 (m, 4H), 1.75-1.58 (m,2H), 0.90-0.76 (m, 2H), 0.71-0.56 (m, 2H).

C146 [C₂₉H₃₀F₂N₆O₂ + H]⁺ 533.2; 533.7; HCl salt; 99.4% at 254 nm (400MHz, CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (s, 1H), 7.63 (dd, J = 8.0, 1.5 Hz,1H), 7.55-7.42 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15-7.03 (m, 3H),3.79 (d, J = 19.8 Hz, 2H), 3.42 (br, s, 2H), 3.30- 3.18 (m, 2H),2.91-2.80 (m, 1H), 2.35-2.21 (m, 5H), 2.19-1.96 (m, 2H), 0.87-0.76 (m,2H), 0.68- 0.58 (m, 2H).

C147 [C₂₉H₃₂FN₇O₂ + H]⁺ 530.3; 530.4; di-HCl salt; 99.4% at 254 nm (400MHz, CD₃OD) δ ppm 9.15 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 5.5 Hz, 1H),8.79-8.70 (m, 1H), 8.45 (s, 1H), 8.32-8.21 (m, 1H), 7.69 (s, 1H), 7.61(d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 3.87 (d, J= 21.8 Hz, 2H), 3.62-3.49 (m, 2H), 3.30-3.23 (m, 1H), 2.94 (s, 3H),2.89-2.79 (m, 1H), 2.31 (s, 8H), 0.82 (dd, J = 7.0, 1.8 Hz, 2H), 0.61(dd, J = 3.8, 2.0 Hz, 2H).

C148 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.22 (s, 1H), 7.51-7.36 (m, 3H), 5.68 (s, 1H), 3.77 (s,2H), 3.37-3.33 (m, 2H), 2.93-2.84 (m, 1H), 2.47 (s, 3H), 2.07-1.95 (m,4H), 1.93-1.72 (m, 4H), 1.34-1.19 (m, 1H), 0.88- 0.78 (m, 2H), 0.69-0.59(m, 4H), 0.45-0.37 (m, 2H).

C149 [C₂₆H₂₈N₆O₂ + H]⁺ 457.2 457.4; TFA salt; 100% at 254 nm (400 MHz,CD₃OD) δ ppm 8.93 (d, J = 7.8 Hz, 2H), 8.57-8.50 (m, 1H), 7.97 (d, J =7.5 Hz, 1H), 7.93 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8Hz, 2H), 6.53 (s, 1H), 3.41 (d, J = 7.0 Hz, 2H), 2.90-2.83 (m, 1H), 2.46(s, 3H), 2.18-2.08 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H), 0.85-0.77 (m, 2H),0.66- 0.59 (m, 2H).

C150 [C₂₈H₃₀N₆O₂ + H]⁺ 483.2 483.2; TFA salt; 100% at 254 nm (400 MHz,CD₃OD) δ ppm 8.88 (d, J = 6.0 Hz, 2H), 8.71 (d, J = 6.0 Hz, 2H), 8.56(s, 1H), 8.12- 8.04 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 6.94 (s,. 1H),4.02-3.94 (m, 2H), 3.53 (d, J = 7.3 Hz, 2H), 3.44 (t, J = 11.5 Hz, 2H),2.92-2.82 (m, 1H), 2.49 (s, 3H), 2.16-2.04 (m, 1H), 1.80 (d, J = 13.1Hz, 2H), 1.53- 1.38 (m, 2H), 0.87-0.79 (m, 2H), 0.67-0.60 (m, 2H).

C151 [C₂₇H₃₁N₇O₂ + H]⁺ 486.3 486.2; free base; 100% at 254 nm (400 MHz,CD₃OD) δ ppm 8.47 (s, 1H), 8.05 (s, 1H), 7.96-7.91 (m, 1H), 7.54 (d, J =2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.52(s, 1H), 4.38 (s, 3H), 4.02-3.92 (m, 2H), 3.50- 3.39 (m, 4H), 2.90-2.82(m, 1H), 2.46 (s, 3H), 2.11-1.99 (m, 1H), 1.82-1.73 (m, 2H), 1.50-1.36(m, 2H), 0.86-0.77 (m, 2H), 0.67-0.59 (m, 2H).

C152 [C₂₆H₂₆N₆O₂ + H]⁺ 455.2 455.2; HCl salt; 95.9% at 254 nm (400 MHz,CD₃OD) δ ppm 9.10 (s, 1H), 8.82 (d, J = 6.0 Hz, 1H), 8.73-8.66 (m, 1H),8.41 (s, 1H), 8.24-8.15 (m, 1H), 7.69 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H),7.23 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 3.39 (d, J = 7.0 Hz, 2H),2.89-2.78 (m, 1H), 2.29 (s, 3H), 1.37-1.23 (m, 1H), 0.86-0.75 (m, 2H),0.70-0.56 (m, 4H), 0.45-0.38 (m, 2H).

C153 [C₂₆H₃₂N₆O₂ + H]⁺ 461.3 461.3; TFA salt; 96.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.70-7.60 (m, 1H), 7.59-7.49 (m, 1H),7.42-7.36 (m, 1H), 5.59-5.51 (m, 1H), 4.11-3.94 (m, 3H), 3.61 (t, J =10.8 Hz, 2H), 3.42-3.34 (m, 2H), 2.91-2.83 (m, 1H), 2.46 (s, 3H),2.12-2.03 (m, 2H), 1.70-1.56 (m, 2H), 1.31-1.21 (m, 1H), 0.87-0.79 (m,2H), 0.69- 0.59 (m, 4H), 0.43-0.36 (m, 2H).

C154 [C₃₀H₃₀N₆O + H]⁺ 491.2 491.2; TFA salt; 99.3% at 254 nm (400 MHz,CD₃OD) δ ppm 9.38 (d, J = 9.5 Hz, 1H), 9.09-9.02 (m, 1H), 8.55 (s, 1H),8.23 (d, J = 8.5 Hz, 1H), 8.12-7.99 (m, 3H), 7.96-7.89 (m, 1H),7.84-7.76 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 3.39 (d, J =7.3 Hz, 3H), 2.88-2.79 (m, 1H), 2.38 (s, 3H), 2.19-2.06 (m, 1H), 1.07(d, J = 6.8 Hz, 6H), 0.84-0.74 (m, 2H), 0.64-0.54 (m, 2H).

C155 [C₂₉H₂₈N₆O + H]⁺ 477.2 477.2; TFA salt; 96.2% at 254 nm (400 MHz,CD₃OD) δ ppm 9.67 (d, J = 8.8 Hz, 1H), 9.22-9.18 (m, 1H), 8.61 (s, 1H),8.34-8.29 (m, 1H), 8.26-8.19 (m, 2H), 8.18-8.13 (m, 2H), 8.04- 7.97 (m,1H), 7.78 (d, J = 8.5 Hz, 2H), 6.63 (s, 1H), 3.41 (d, J = 7.0 Hz, 2H),2.87-2.79 (m, 1H), 2.19- 2.07 (m, 1H), 1.07 (d, J = 6.5 Hz, 6H),0.84-0.76 (m, 2H), 0.66-0.59 (m, 2H).

C156 [C₂₇H₃₄N₆O₃ + H]⁺ 491.3 491.2; HCl salt; 96.2% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.49-7.38 (m, 3H), 5.63 (s, 1H), 4.16-4.07(m, 1H), 4.04-3.92 (m, 3H), 3.67-3.56 (m, 4H), 2.92-2.83 (m, 1H), 2.47(s, 5H), 2.31-2.16 (m, 1H), 2.11-2.00 (m, 2H), 1.80-1.57 (m, 4H),0.86-0.78 (m, 2H), 0.66-0.59 (m, 2H).

C157 [C₂₇H₃₆N₆O₂ + H]⁺ 477.3 477.3; HCl salt; 100% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.53-7.33 (m, 3H), 5.78-5.50 (m, 1H), 3.98(s, 2H), 3.48-3.33 (m, 2H), 2.93-2.82 (m, 1H), 2.47 (s, 3H), 2.20-2.03(m, 1H), 1.74 (br, s, 6H), 1.62-1.39 (m, 2H), 1.05 (d, J = 5.5 Hz, 6H),0.82 (d, J = 6.3 Hz, 2H), 0.63 (d, J = 2.3 Hz, 2H).

C158 [C₂₆H₃₆N₆O₂ + H]⁺ 465.3 465.4; HCl salt; 100% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.51-7.38 (m, 3H), 5.67 (br, s, 1H),3.93-3.57 (m, 3H), 2.91- 2.83 (m, 1H), 2.47 (s, 3H), 2.16-1.99 (m, 2H),1.12-1.00 (m, 12H), 0.86-0.78 (m, 2H), 0.66-0.56 (m, 2H).

C159 [C₂₇H₂₈N₆O₃ + H]⁺ 485.2 485.2; HCl salt; 98.6% at 254 nm (400 MHz,CD₃OD) δ ppm 9.14 (s, 1H), 8.85 (d, J = 5.5 Hz, 1H), 8.79-8.72 (m, 1H),8.40 (s, 1H), 8.30-8.21 (m, 1H), 7.68 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H),7.23 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 4.17-4.06 (m, 1H), 3.54 (d, J =6.5 Hz, 2H), 2.88- 2.78 (m, 1H), 2.53-2.43 (m, 2H), 2.29 (s, 4H),1.81-1.68 (m, 2H), 0.84-0.77 (m, 2H), 0.62-0.56 (m, 2H).

C160 [C₂₆H₂₉N₇O + H]⁺ 456.2 457.2; HCl salt; 98.8% al 254 nm (400 MHz,CD₃OD) δ ppm 9.70 (s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.42-8.34 (m, 1H),8.31 (s, 1H), 8.02-7.93 (m, 1H), 7.88-7.77 (m, 2H), 7.43 (d, J = 8.3 Hz,1H), 3.24 (d, J = 6.8 Hz, 2H), 2.94-2.84 (m, 1H), 2.47 (s, 3H),2.17-2.02 (m, 1H), 1.06 (d, J = 6.8 Hz, 6H), 0.90-0.80 (m, 2H),0.70-0.60 (m, 2H).

C161 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3 505.3; HCl salt; 95.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.24 (s, 1H), 7.52-7.36 (m, 3H), 5.52 (br, s, 1H), 4.31(br, s, 1H), 4.02-3.93 (m, 2H), 3.89-3.81 (m, 1H), 3.80-3.65 (m, 3H),3.53-3.38 (m, 4H), 2.91-2.82 (m, 1H), 2.45 (s, 3H), 2.33-2.20 (m, 1H),2.18-2.02 (m, 3H), 1.97-1.88 (m, 1H), 1.79-1.69 (m, 2H), 1.50-1.37 (m,2H), 0.87-0.78 (m, 2H), 0.66-0.57 (m, 2H).

C162 [C₂₉H₃₆N₆O₃ + H]⁺ 517.3 517.3; free base; 96.2% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.94 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.30(d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.14-4.03 (m, 4H), 4.01-3.92 (m, 2H),3.50-3.39 (m, 3H), 3.27 (s, 2H), 2.89-2.80 (m, 1H), 2.65-2.54 (m, 2H),2.44 (s, 3H), 2.22-2.11 (m, 2H), 2.05-1.93 (m, 1H), 1.80-1.70 (m, 2H),1.47- 1.32 (m, 2H), 0.85-0.76 (m, 2H), 0.66-0.57 (m, 2H).

C163 [C₃₁H₄₂N₆O₃ + H]⁺ 547.3; 547.3 HCl salt; 97.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.55-7.32 (m, 3H), 5.68 (br, s, 1H), 3.97 (d,J = 11.5 Hz, 2H), 3.90-3.51 (m, 3H), 3.42 (t, J = 11.2 Hz, 4H), 2.93-2.78 (m, 1H), 2.46 (s, 3H), 2.15-1.97 (m, 1 H), 1.93-1.63 (m, 8H),1.50-1.07 (m, 7H), 0.86-0.77 (m, 2H), 0.69-0.55 (m, 2 H).

C164 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 99.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.31 (d, J = 8.0Hz, 1H), 5.35 (s, 1H), 4.44-4.29 (m, 1H), 3.97 (dd, J = 11.3, 3.8 Hz,2H), 3.86-3.77 (m, 1H), 3.76-3.58 (m, 2H), 3.53- 3.38 (m, 3H), 3.28 (d,J = 7.0 Hz, 2H), 2.90-2.79 (m, 1H), 2.44 (s, 3H), 2.21-1.91 (m, 5H),1.76 (d, J = 12.5 Hz, 2H), 1.49-1.32 (m, 2H), 0.81 (dd, J = 7.0, 1.8 Hz,2H), 0.62 (dd, J = 4.0, 2.0 Hz, 2H).

C165 [C₃₀H₄₀N₆O₃ + H]⁺ 533.3; 534.3; HCl salt; 96.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1 H), 7.58-7.24 (m, 3H), 5.68 (br, s, 1H),4.10-3.60 (m, 5H), 3.45- 3.38 (m, 4H), 2.87 (br, s, 1 H), 2.46 (s, 3H),2.31- 1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.54 (m, 6H), 1.50-1.25 (m,4H), 0.82 (d, J = 6.0 Hz, 2H), 0.62 (br, s, 2H).

C166 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 99.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 8.06-7.82 (m, 2 H), 7.30 (d, J = 7.8 Hz, 1H),5.25 (s, 1H), 3.97 (d, J = 7.5 Hz, 2H), 3.84-3.51 (m, 5H), 3.43 (t, J =11.4 Hz, 2H), 3.26 (d, J = 6.5 Hz, 2H), 2.94- 2.77 (m, 1H), 2.62-2.50(m, 1H), 2.44 (s, 3H), 2.23-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.81(m, 1H), 1.76 (d, J = 12.5 Hz, 2H), 1.48-1.31 (m, 2H), 0.88-0.73 (m,2H), 0.68-0.52 (m, 2H).

C167 [C₂₈H₃₆N₆O₃ + H]⁺ 505.3; 505.3; HCl salt; 97.7% at 254 nm (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 8.06-7.82 (m, 2 H), 7.30 (d, J = 7.8 Hz, 1H),5.25 (s, 1H), 3.97 (d, J = 7.5 Hz, 2H), 3.84-3.51 (m, 5H), 3.43 (t, J =11.4 Hz, 2H), 3.26 (d, J = 6.5 Hz, 2H), 2.94- 2.77 (m, 1H), 2.62-2.50(m, 1H), 2.44 (s, 3H), 2.23-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.81(m, 1H), 1.76 (d, J = 12.5 Hz, 2H), 1.48-1.31 (m, 2H), 0.88-0.73 (m,2H), 0.68-0.52 (m, 2H).

C168 [C₂₉H₃₉N₇O₂ + H]⁺ 518.3; 518.4; di-HCl salt; 99.0% at 254 nm (400MHz, CD₃OD) δ ppm 8.22 (s, 1H), 7.65-7.20 (m, 3H), 6.24-5.48 (m, 2H),4.46-4.28 (m, 1H), 4.19-3.96 (m, 2H), 3.94-3.62 (m, 1H), 3.59-3.38 (m,4H), 3.25-3.08 (m, 1H), 2.87 (br, s, 1H), 2.47 (s, 3H), 2.19 (br, s,4H), 2.00-1.45 (m, 7H), 0.97- 0.74 (m, 2H), 0.71-0.50 (m, 2H).

C169 [C₂₈H₃₆FN₇O + H]⁺ 506.3; 506.4; di-HCl salt; 98.0% at 254 nm (400MHz, CD₃OD) δ ppm 8.22 (br, s, 1H), 7.57- 7.33 (m, 3H), 5.76 (br, s,1H), 4.34-4.12 (m, 1H), 4.05-3.79 (m, 2H), 3.53-3.37 (m, 2H), 3.28-3.15(m, 2H), 2.94-2.81 (m, 1H), 2.47 (s, 3H), 2.35-1.98 (m, 6H), 1.91-1.57(m, 6H), 0.82 (m, J = 6.3 Hz, 2H), 0.68-0.54 (m, 2H).

C170 [C₂₉H₃₈FN₇O + H]⁺ 520.3; 520.4; di-HCl salt; 98.0% at 254 nm (400MHz, CD₃OD) δ ppm 8.23 (s, 1H), 7.53-7.33 (m, 3H), 5.75 (br, s, 1H),4.34-4.11 (m, 1H), 4.03- 3.80 (m, 2H), 3.64-3.44 (m, 3H), 3.00-2.79 (m,4H), 2.47 (s, 3H), 2.39-2.06 (m, 6H), 1.92-1.55 (m, 7H), 0.88-0.76 (m,2H), 0.62 (m, J = 1.8 Hz, 2H).

C171 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 98.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.16 (s, 1H), 8.08 (s, 1H), 7.89 (dd, J = 8.2, 1.6 Hz, 1H),7.29 (d, J = 8.0 Hz, 1H), 5.30 (s, 1H), 4.42-4.25 (m, 1H), 4.15- 4.02(m, 1H), 2.86-2.83 (m, J = 7.4 Hz, 1H), 2.51- 2.45 (m, 2H), 2.44 (s,3H), 2.22-2.04 (m, 3H), 1.83-1.51 (m, 8H), 0.87-0.76 (m, 2H), 0.68- 0.55(m, 2H).

C172 [C₂₇H₃₄N₆O₂ + H]⁺ 475.3; 475.4; HCl salt; 97.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 7.55-7.29 (m, 3H), 5.54 (br, s, 1H),4.50-4.37 (m, 1H), 4.26- 4.07 (m, 1H), 3.62 (d, J = 6.8 Hz, 2H),2.92-2.83 (m, 1H), 2.75-2.61 (m, 1H), 2.46 (s, 3H), 2.31-2.02 (m, 6H),1.92-1.56 (m, 6H), 0.91-0.75 (m, 2H), 0.71-0.52 (m, 2H).

C173 [C₂₈H₃₅FN₆O₂ + H]⁺ 507.3; 507.4; HCl salt; 98.0% at 254 nm (400MHz, CD₃OD) δ ppm 8.33 (s, 1H), 7.80-7.52 (m, 2H), 7.39 (br, s, 1H),5.49 (br, s, 1H), 4.10-3.80 (m, 2H), 3.53-3.38 (m, 3H), 3.28-3.05 (m,2H), 2.88 (br, s, 1H), 2.45 (s, 3H), 2.33-1.57 (m, 12H), 0.92-0.75 (m,2H), 0.70-0.50 (m, 2H).

C174 [C₂₉H₃₇FN₆O₂ + H]⁺ 521.3; 521.5; HCl salt; 98.0% at 254 nm (400MHz, CD₃OD) δ ppm 8.33 (s, 1H), 7.86 (br, s, 1H), 7.76 (d, J = 5.8 Hz,1H), 7.34 (d, J = 7.5 Hz, 1H), 5.86 (br, s, 1H), 5.50 (br, s, 1H), 3.81(d, J = 19.8 Hz, 2H), 3.64-3.38 (m, 2H), 3.25-3.13 (m, 2H), 2.99-2.72(m, 5H), 2.44 (s, 3H), 2.34-2.00 (m, 6H), 1.98-1.56 (m, 6H), 0.92-0.72(m, 2H), 0.67- 0.44 (m, 2H).

C175 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 96.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.21 (s, 1H), 7.54-7.38 (m, 3H), 5.57 (s, 1H), 4.00-3.86(m, 3H), 3.81-3.55 (m, 4H), 3.44 (d, J = 7.0 Hz, 2H), 2.93-2.82 (m, 1H),2.48 (s, 3H), 2.15-1.49 (m, 13H), 0.91-0.78 (m, 2H), 0.69-0.52 (m, 2H).

C176 [C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.2 TFA salt; 98.6% at 254 nm (400 MHz,CD₃OD) δ ppm 8.91 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 5.3 Hz, 1H),8.44-8.32 (m, 2H), 8.06-7.91 (m, 1H), 7.70 (s, 1H), 7.58 (d, J = 8.3 Hz,1H), 7.21 (d, J = 8.0 Hz, 1H), 5.98 (s, 1H), 4.01-3.84 (m, 1H), 3.38 (d,J = 7.0 Hz, 2H), 2.88- 2.79 (m, 1H), 2.28 (s, 3H), 1.96-1.51 (m, 9H),0.84-0.76 (m, 2H), 0.64-0.58 (m, 2H).

C177 [C₂₉H₃₂N₆O₃ + H]⁺ 513.3; 513.2 HCl salt; 99.8% at 254 nm (400 MHz,CD₃OD) δ ppm 9.05-8.87 (m, 1H), 8.74 (d, J = 5.5 Hz, 1H), 8.42-8.51 (m,1H), 8.39 (s, 1H), 8.09-8.00 (m, 1H), 7.70 (s, 1H), 7.59 (d, J = 8.0 Hz,1H), 7.22 (d, J = 8.0 Hz, 1H), 6.00 (s, 1H), 3.62-3.48 (m, 1H),3.44-3.33 (m, 2H), 2.87- 2.79 (m, 1H), 2.29 (s, 3H), 2.22-2.10 (m, 1H),2.09-1.49 (m, 4H), 1.40-1.05 (m, 4H), 0.93-0.75 (m,2H), 0.67-0.53 (m,2H).

C178 [C₃₀H₃₄FN7O₂ + H]⁺ 544.3; 544.3 di-TFA salt; 96.5% at 254 nm (4400MHz, CD₃OD) δ ppm 8.38 (s, 1H), 7.85 (s, 1H), 7.64 (dd, J = 7.80, 1.5Hz, 1H), 7.55-7.45 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.18-6.97 (m, 3H),5.92 (s, 1H), 3.62 (t, J = 6.3 Hz, 2H), 2.92 (s, 3H), 2.89 (t, J = 6.0Hz, 2H), 2.86-2.79 (m, 1H), 2.28 (s, 3H), 0.84-0.78 (m, 2H), 0.64-0.57(m, 2H); 8H peaks due to the piperazine are either very broad orobscured by the peaks due the solvent and H₂O at 3.33 ppm and/or 4.88pm.

C179 [C₂₉H₃₈N₆O₃ + H]⁺ 519.3; 519.3 TFA salt; 99.4% at 254 nm (400 MHz,CD₃OD) δ ppm 8.20 (s, 1H), 7.64-7.47 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H),5.58 (s, 1H), 4.10-3.92 (m, 4H), 3.70-3.56 (m, 2H), 3.43 (d, J = 6.0 Hz,2H), 2.95-2.83 (m, 1H), 2.47 (s, 3H), 2.13- 2.04 (m, 2H), 1.93-1.74 (m.,3H), 1.72-1.48 (m, 8H), 0.91-0.79 (m, 2H), 0.69-0.57 (m, 2H).

C180 [C₃₀H₃₃FN₆O₂ + H]⁺ 529.3; 529.3 TFA salt; 97.1% at 254 nm (400 MHz,CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (s, 1H), 7.67-7.58 (m, 1H), 7.56-7.41(m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16-7.01 (m, 3H), 6.01 (s, 1H), 3.90(t, J = 6.3 Hz, 2H), 3.74-3.57 (m, 2H), 3.48 (t J = 6.3 Hz, 2H),3.11-2.99 (m, 2H), 2.90-2.75 (m, 1H), 2.27 (s, 3H), 2.03-1.92 (m, 2H),1.92-1.73 (m, 3H), 1.66-1.48 (m, 1H), 0.81 (s, 2H), 0.68-0.52 (m, 2H).

C181 [C₂₉H₃₁FN₆O₃ + H]⁺ 530.2; 530.3 TFA salt; 97.9% at 254 nm (400 MHz,CD₃OD) δ ppm 8.35 (s, 1H), 7.79 (s, 1H), 7.59 (dd, J = 8.0, 1.8 Hz, 1H),7.30-7.14 (m, 5H), 5.98 (s, 1H), 4.17-3.98 (br. s., 2H), 3.91 (t, J =6.3 Hz, 2H), 3.98-3.74 (br.s. 2H), 3.55 (t, J = 6.2 Hz, 3H), 3.74-3.45(br.s, 2H) 3.40-3.15 (br.s. 2H), 2.87-2.80 (m, 1H), 2.26 (s, 3H),0.85-0.77 (m, 2H), 0.66-0.54 (m, 2H).

C182 [C₃₀H₃₃FN₆O₃ + H]⁺ 545.3 545.3; TFA salt; 98.5% at 254 nm (400 MHz,CD₃OD) δ ppm 8.36 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 9.3 Hz, 1H),7.53-7.41 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16-7.02 (m, 3H), 5.98 (s,1H), 4.18-4.05 (m, 0.5H), 3.89 (br. s., 2.5H), 3.79-3.65 (m, 1H), 3.49(br. s., 3H), 3.45-3.34 (m, 1H), 3.21-3.07 (m, 1H), 2.88-2.77 (m, 1H),2.27 (s, 3H), 2.23-1.67 (m, 4H), 0.85-0.77 (m, 2H), 0.66- 0.55 (m, 2H).

C183 [C₃₀H₄₁N₇O₃ + H]⁺ 548.3; 548.4 TFA salt; 98.3% at 254 nm (400 MHz,CD₃OD) δ ppm 8.22 (s, 1H), 7.60-7.35 (m, 3H), 5.79 (s, 1H), 4.14-3.93(m, 4H), 3.92-3.63 (m, 2H), 3.60-3.49 (m, 3H), 3.48-3.37 (m, 1H),3.23-3.07 (m, 1H), 2.87 (s, 1H), 2.48 (s, 3H), 2.25- 1.39 (m, 12H),0.88-0.79 (m, 2H), 0.68-0.61 (m, 2H).

C184 [C₂₉H₃₇F₂N₇O + H]⁺ 538.3; 538.4 TFA salt; 97.8% at 254 nm (400 MHz,CD₃OD) δ ppm 8.19 (s, 1H), 7.52-7.37 (m, 3H), 5.69 (s, 1H), 4.29-4.20(m, 1H), 4.10-3.99 (m, 2H), 3.72-3.46 (m, 6H), 2.94-2.80 (m, 1H), 2.46(s, 3H), 2.44-2.33 (m, 4H), 2.24-2.06 (m, 2H), 1.91-1.58 (m, 6H),0.89-0.77 (m, 2H), 0.69-0.51 (m, 2H).

C185 [C₂₈H₃₂F₂N₈O₂ + H]⁺ 551.3: 551.4 HCl salt; 98.1% at 254 nm (400MHz, CD₃OD) δ ppm 8.42 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.75 (d, J =7.8 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.02 (s, 1H), 4.00-3.91 (m, 5H), 3.85 (br. s., 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.42 (br. s.,2H), 2.93-2.76 (m, 1H), 2.52-2.32 (m, 7H), 0.86-0.75 (m, 2H), 0.69-0.55(m, 2H).

C186 [C₂₈H₃₆N₆O₂ + H]⁺ 489.3; 489.4 TFA salt; 98.2% at 254 nm (400 MHz,CD₃OD) δ ppm 8.18 (s, 1H), 7.48-7.36 (m, 3H), 5.52 (s, 1H), 4.23-4.10(m, 1H), 3.65-3.57 (m, 2H), 2.93-2.75 (m, 2H), 2.46 (s, 3H), 2.31-2.21(m, 2H), 2.20-2.11 (m, 3H), 2.06-1.89 (m, 2H), 1.89-1.50 (m, 6H), 1.37(s, .3H), 0.87-0.79 (m, 2H), 0.68-0.56 (m, 2H).

C187 [C₂₇H₂₉FN₆O₂ + H]+ 489.2; 489.2 TFA salt; 94.0% at 254 nm (400 MHz,CD₃OD) δ ppm 8.39 (s, 1H), 7.83 (d, J = 0.5 Hz, 1H), 7.70-7.59 (m, 1H),7.55-7.45 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.15-6.98 (m, 3H), 6.05 (s,1H), 3.90 (t, J = 6.3 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.02 (s, 6H),2.84 (s, 1H), 2.27 (s, 3H), 0.85-0.75 (m, 2H), 0.66-0.57 (m, 2H).

Example B: TTK Inhibition Assay

Active TTK was purchased from Invitrogen as an amino terminal GST fusionof full length human TTK. Amino terminal 6 histidine, sumo tagged humanTTK (residues 1-275) was expressed in E. coli, and purified to >95%homogeneity by Ni²⁺ agarose, gel filtration, and ion exchangechromatography.

TTK activity was measured using an indirect ELISA detection system.GST-TTK (0.68 nM) was incubated in the presence of either 16 μM ATP(Sigma cat# A7699) or 100 μM ATP, 50 mM Hepes pH 7.2, 1 mM EGTA, 10 mMMgCl₂, and 0.1% Pluronic in a 96 well microtitre plate pre-coated withamino terminal 6 histidine, sumo tagged TTK (amino acid residues 1-275).

The reaction was allowed to proceed for 30 minutes, followed by 5 washesof the plate with Wash Buffer (phosphate buffered saline supplementedwith 0.2% Tween 20), and incubation for 30 minutes with a 1:3000dilution of primary antibody (Cell Signaling cat#9381). The plate waswashed 5 times with Wash Buffer, incubated for 30 minutes in thepresence of secondary antibody coupled to horse radish peroxidase(BioRad cat#1721019, 1:3000 concentration), washed an additional 5 timeswith Wash Buffer, and incubated in the presence of TMB substrate (Sigmacat# T0440). The colourimetric reaction was allowed to continue for 5minutes, followed by addition of stop solution (0.5 N sulphuric acid),and quantified by detection at 450 nm with either a monochromatic orfilter based plate reader (Molecular Devices M5 or Beckman DTX880,respectively).

Compound inhibition was determined at either a fixed concentration (10μM) or at a variable inhibitor concentration (typically 0.5 μM to 0.001μM in a 10 point dose response titration). Compounds were pre-incubatedin the presence of enzyme for 5 minutes prior to addition of ATP and theactivity remaining quantified using the above described activity assay.The % Inhibition of a compound was determined using the followingformula; % Inhibition=100×(1−(experimental value−background value)/(highactivity control−background value)). The IC₅₀ value was determined usinga non-linear 4 point logistic curve fit (XLfit4, IDBS) with the formula;(A+(B/(1+((x/C)^D)))), where A=background value, B=range, C=inflectionpoint, D=curve fit parameter.

In Table 1 and 2 below, IC₅₀ value ranges for compound examples aregiven using 16 μM ATP (Sigma cat# A7699). The IC₅₀ ranges are indicatedas “A,” “B,” and “C,” for values less than or equal to 0.1 μM; thosegreater than 0.1 μM and less than or equal to 0.5 μM; and those greaterthan 0.5 μM, respectively. IC₅₀ ranges denoted with an asteriskindicated that 16 μM ATP (Sigma cat# A7699) was used in the assay.

In Table 3 below, IC₅₀ value ranges for exemplary compounds are givenusing 100 μM ATP. The IC₅₀ ranges are indicated as “A,” “B,” and “C,”for values less than or equal to 0.1 μM; those greater than 0.1 μM andless than or equal to 0.5 μM; and those greater than 0.5 μM,respectively. IC₅₀ ranges denoted with an asterisk indicated that 16 μMATP (Sigma cat# A7699) was used in the assay.

Example C: Cancer Cell Line Data on Exemplary Compounds of the Invention

Breast cancer cells (MDA-MB-231 and MDA-MB-468), colon cancer cells(HCT116) and ovarian cancer cells (PA-1 and OVCAR-3) were seeded (1000to 4000 in 80 μl per well depending on the cell growth rate) into 96well plates 24 hours before compound overlay. Compounds were prepared as10 mM stock solutions in 100% DMSO which were diluted with DMEM(Dulbecco's Modified Eagle's Medium) cell growth Medium (Invitrogen,Burlington, ON, Canada) containing 10% FBS (Fetal Bovine Serum) toconcentrations ranging from 50 nM to 250 μM. Aliquots (20 μl) from eachconcentration were overlaid to 80 μl of the pre-seeded cells in the 96well plates to make final concentrations of 10 nM to 50 μM. The cellswere cultured for 5 days before the Sulforhodamine B assay (SRB) wasperformed to determine the compound's cell growth inhibition activity.

Sulforhodamine B (purchased from Sigma, Oakville, ON, Canada) is awater-soluble dye that binds to the basic amino acids of the cellularproteins. Thus, colorimetric measurement of the bound dye provides anestimate of the total protein mass that is related to the cell number.the cells are fixed in situ by gently aspirating off the culture mediaand adding 50 μl ice cold 10% Trichloroacetic Acid (TCA) per well andincubate at 4° C. for 30-60 min, The plates are washed with H₂O fivetimes and allowed to air dry for 5 min. Addition of 50 μl 0.4% (w/v) SRBsolution in 1% (v/v) acetic acid to each well and incubation for 30 minat RT completes the staining reaction. Following staining, plates arewashed four times with 1% acetic acid to remove unbound dye and thenallowed to air dry for 5 min. The stain is solubilized with 100 μl of 10mM Tris pH 10.5 per well. Absorbance is read at 570 nm.

The percentage (%) of relative growth inhibition was calculated bycomparing to DMSO treated only cells (100%). GI₅₀'s were determined forcompounds with cytotoxic activity. The GI₅₀ was calculated usingGraphPad PRISM software (GraphPad Software, Inc., San Diego, Calif.,USA). GI₅₀ (growth inhibition) is the compound concentration that causes50% inhibition of cell growth.

In Table 1 below, GI₅₀ value ranges for compound examples against breastcancer cell lines (MDA-MB-468), colon cancer cell lines (HCT116) andovarian cancer cell lines (PA-1) are given. The example compoundsdemonstrated varying growth inhibition/cell killing activity againstcells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ranges are indicated as “A,” “B,” and “C,” for values less than or equalto 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM;and those greater than 0.5 μM, respectively.

In Table 2 below, GI₅₀ value ranges for compound examples against breastcancer cell lines (MDA-MB-231), colon cancer cell lines (HCT116) andovarian cancer cell lines (PA-1) are given. The example compoundsdemonstrated varying growth inhibition/cell killing activity againstcells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ranges are indicated as “A,” “B,” and “C,” for values less than or equalto 0.1 μM; those greater than 0.1 μM and less than or equal to 0.5 μM;and those greater than 0.5 μM, respectively.

In Table 3 below, GI₅₀ value ranges for compound examples against breastcancer cell lines (MDA-MB-468), colon cancer cell lines (HCT116) andovarian cancer cell lines (OVCAR-3) are given. The example compoundsdemonstrated varying growth inhibition/cell killing activity againstcells of breast cancer, colon cancer, and ovarian cancer. The GI₅₀ranges are indicated as “A,” “B,” and “C,” for values less than or equalto 0.1 μM; those greater than 0.1 τM and less than or equal to 0.5 μM;and those greater than 0.5 μM, respectively.

Example D: Colon and Ovarian Cancer Tumor-Initiating Cell Data ofExemplary Compounds

Materials and Methods:

Non-tissue or tissue cultured treated T-75 flask and 96-well plates werepurchased from VWR. Vitamin B-27 supplement, MEM NEAA (minimum essentialmedium non essential amino acids), sodium pyruvate, L-glutamine, N2supplement, penicillin-streptomycin and fungizone/amphotericin B wereobtained from Invitrogen. Lipid mixture, heparin and EGF were purchasedfrom Sigma; bFGF from BD Biosciences. Tumor Initiating Cells (TICs) fromcolon were routinely maintained using non-tissue cultured treated T-75flasks in DMEM:F12 medium containing 0.2×B-27 supplement, 4 ug/mlheparin, 1×MEM NEAA, 1× sodium pyruvate, 1 mM glutamine, 10 pg/ul bFGF,20 pg/ul EGF, 1×N2 supplement, lipid mixture, penicillin-streptomycinand fungizone/amphotericin B. Ovarian TICs were routinely maintainedusing tissue cultured treated T-75 flasks in DMEM:F12 medium containing1×B-27 supplement, 4 ug/ml heparin, 20 pg/ul bFGF, 20 pg/ul EGF andpenicillin-streptomycin.

Assay Protocol:

Compounds described herein were dissolved in DMSO and further diluted incell culture medium for GI₅₀ determination. Colon TICs were trypsinizedand seeded into non-tissue cultured treated 96-well plates with 4,000cells/well. After 24 h, compound was added into the cell culture atdifferent concentrations, and the final concentration of DMSO wasadjusted to 0.1%. Cells were then cultured at 37° C. for 9 days. OvarianTICs were trypsinized and seeded into tissue cultured treated 96-wellplates with 1,000 cells/well. After 24 h, compound was added into thecell culture at different concentrations, and the final concentration ofDMSO was adjusted to 0.1%. Cells were then cultured at 37° C. for 6days. Cell viability was assessed by Alamar Blue assay: 10 ul of AlamarBlue was added into each well. After 4 hours incubation at 37° C.,fluorescence was recorded at excitation 544 and emission 590. GI₅₀(Growth inhibition) was calculated using GraphPad Prism 4.0 software.Cell growth inhibition data for compounds described herein is tabulatedbelow.

In Table 1 below, GI₅₀ value ranges for compound examples against TICs(Colon 12 and Ovarian 2393A) are given. The GI₅₀ ranges are indicated as“A,” “B,” and “C,” for values less than or equal to 0.1 μM; thosegreater than 0.1 μM and less than or equal to 0.5 μM; and those greaterthan 0.5 μM, respectively.

TABLE 1 In vitro activity of Compound Examples Tumor Cancer Cell LineInitiating Cell TTK GI₅₀ Range GI₅₀ Range Example IC₅₀ MDA- Ovarian #Range HCT116 MB-468 PA-1 2393A Colon 12 A1 B* ND ND ND ND ND A2 A* B B AB A A3 A* A A A B A A4 A* B B B B A A5 A* B C B C B A6 A* B C A B B A7A* C C B C C A8 C* C C C ND ND A9 C* ND ND ND ND ND A10 A* B C B ND NDA11 A* B C B ND ND A12 C* C C C ND ND A13 A* C C B ND ND A14 A* B C B CC A15 A* B C B B B ND—not determined IC₅₀ ranges denoted with anasterisk indicated that 16 μM ATP (Sigma cat# A7699) was used in theassay.

TABLE 2 In vitro activity of Compound Examples Tumor Cancer Cell LineInitiating Cell TTK GI₅₀ Range GI₅₀ Range Example IC₅₀ MDA- Ovarian #Range HCT116 MB-231 PA-1 2393A Colon 12 B2 A* C C B C B B3 A* A B A B BB1 A* A A A A A B4 A* ND ND ND ND ND B5 A* A A A A A B14 A* A A A A AB15 C* ND ND ND ND ND B6 A* B B A B B B16 A* A A A A A B18 A* A B A A AB7 A* A A A A A B8 A* B B A B B B19 A* B B A B B B20 A* A A A A A B17 A*A A A A A B9 A* A A A A A B10 A* B C B ND ND B11 A* B B B ND ND B12 A* AA A A A B13 A* A A A B A B29 A* B C B C B B21 A* A B A ND ND B22 A* A AA ND ND B25 A* A A A ND ND B23 A* B B B ND ND B26 A* A B A ND ND B24 A*A A A ND ND B31 A* A A A ND ND B30 A* ND ND ND ND ND B27 A* ND ND ND NDND B28 A* ND ND ND ND ND B32 A* ND ND ND ND ND B33 A* ND ND ND ND NDND—not determined IC₅₀ ranges denoted with an asterisk indicated that 16μM ATP (Sigma cat# A7699) was used in the assay.

TABLE 3 In vitro activity of Compound Examples Tumor Initiating CellGI₅₀ Cancer Cell Line GI₅₀ Range Range Exam- TTK IC₅₀ MDA- OVCAR-Ovarian Colon ple # Range MB-468 HCT116 3 2393A 12 C1 A* ND ND ND ND NDC2 B* ND ND ND ND ND C3 C* ND ND ND ND ND C4 B* ND ND ND ND ND C5 C* NDND ND ND ND C6 A* ND ND ND ND ND C7 A* C C C B B C8 A* B B B ND ND C9 A*C C B ND ND C10 A* C C C C C C11 A* C C C B B C12 A* ND ND ND ND ND C13A* B B C ND ND C14 A* A A A A A C15 A* ND ND ND ND ND C16 A* ND ND ND NDND C17 C* ND ND ND ND ND C18 C* ND ND ND ND ND C19 A* B C C ND ND C20 A*B A B B A C21 A* A A A A A C22 A* B B B ND ND C23 A* C B C ND ND C24 A*A A A A A C25 A* B A B B A C26 A* B A B A A C27 A* B A B ND ND C28 A A AA A A C29 A ND ND ND ND ND C30 A C C C ND ND C31 A A A A A A C32 A A A AA A C33 A A A A ND ND C34 A A A A ND ND C35 A A A A ND ND C36 A A A A NDND C37 A A A A A A C38 A A A A A A C39 A A A A A A C40 A A A B B A C41 AA A A B A C42 A A A A A A C43 A A A A ND ND C44 A A A A ND ND C45 A A AA B A C46 A A A B A A C47 A A A A ND ND C48 A B B B B B C49 A B B B NDND C50 C ND ND ND ND ND C51 A B B B ND ND C52 A B B C ND ND C53 A ND NDND ND ND C54 A B B B ND ND C55 A B A B ND ND C56 A A A A ND ND C57 A B BB ND ND C58 A B A B ND ND C59 A B B B ND ND C60 A ND ND ND ND ND C61 A AA A ND ND C62 A B B B ND ND C63 A ND ND ND ND ND C64 A ND ND ND ND NDC65 A ND ND ND ND ND C66 A B B B ND ND C67 A ND ND ND ND ND C68 A B C BND ND C69 B ND ND ND ND ND C70 A ND ND ND ND ND C71 A B B C ND ND C72 AA A B ND ND C73 A ND ND ND ND ND C74 A B B C ND ND C75 A ND ND ND ND NDC76 A ND ND ND ND ND C77 A B B B ND ND C78 A B B B ND ND C79 A C C C NDND C80 A ND ND ND ND ND C81 A ND ND ND ND ND C82 A B B B ND ND C83 A B AB ND ND C84 A ND ND ND ND ND C85 A B B B ND ND C86 B ND ND ND ND ND C87A B B C ND ND C88 A B C C ND ND C89 A C B C ND ND C90 A B B C ND ND C91A ND ND ND ND ND C92 A C B C ND ND C93 A ND ND ND ND ND C94 A C C C NDND C95 A C B C ND ND C96 A C C C ND ND C97 A B A B ND ND C98 A C B C NDND C99 A C B C ND ND C100 A B B B A A C101 B ND ND ND ND ND C102 A ND NDND ND ND C103 A B A B ND ND C104 A B A B ND ND C105 A A A A ND ND C106 BND ND ND ND ND C107 A B B C ND ND C108 A B A A ND ND C109 A B A B ND NDC110 A ND ND ND ND ND C111 A B B B ND ND C112 A ND ND ND ND ND C113 A BB B ND ND C114 A C C C ND ND C115 A ND ND ND ND ND C116 A B A B B B C117A ND ND ND ND ND C118 A B A B B B C119 A ND ND ND ND ND C120 A B B C C CC121 A B B C ND ND C122 A ND ND ND ND ND C123 A A A B ND ND C124 A B B BND ND C125 A A A B ND ND C126 A A A A ND ND C127 A B A B ND ND C128 A NDND ND ND ND C129 A ND ND ND ND ND C130 A B A B A A C131 A B B C ND NDC132 A B C C ND ND C133 A B B B ND ND C134 A B B B ND ND C135 A A A B NDND C136 A A A B ND ND C137 A ND ND ND ND ND C138 A B A B ND ND C139 A BB B ND ND C140 A ND ND ND ND ND C141 A B A B ND ND C142 B ND ND ND ND NDC143 B C C C ND ND C144 A A A A A A C145 A B B B B B C146 A A A B A AC147 A B B C ND ND C148 A B B C ND ND C149 B ND ND ND ND ND C150 A B B BB B C151 A B A B ND ND C152 A A A A ND ND C153 A B A B ND ND C154 B NDND ND ND ND C155 C ND ND ND ND ND C156 A B B B ND ND C157 A A A A ND NDC158 A B A B ND ND C159 A A A A ND ND C160 A ND ND ND ND ND C161 A B A BND ND C162 A ND ND ND ND ND C163 A B A B ND ND C164 A B B C ND ND C165 AB A B B A C166 A ND ND ND ND ND C167 A ND ND ND ND ND C168 A ND ND ND NDND C169 A C B C ND ND C170 A B B C ND ND C171 A A A B ND ND C172 A A A AND ND C173 A C B C ND ND C174 A C B C ND ND C175 A A A B B B C176 A A AA A A C177 A B B B A A C178 A A A B ND ND C179 A A A A ND ND C180 A B AB ND ND C181 A B A B ND ND C182 A A A A A A C183 A B C C ND ND C184 A NDND ND ND ND C185 A ND ND ND ND ND C186 A B A B ND ND C187 A A A B A AND—not determined IC₅₀ ranges denoted with an asterisk indicated that 16μM ATP (Sigma cat# A7699) was used in the assay.

What is claimed is:
 1. A compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—NR^(a1)R^(b1), oR^(c1), sR^(c1), SOR^(c1), or −SO₂R^(c1); R² isNR^(a2)R^(b2), OR^(c2), —SR^(c2), optionally substituted phenyl oroptionally substituted 5-10 membered heteroaryl; R³ is C(═O)NR^(d)R^(e)or NHC(═O)R⁵; each R⁴ is independently selected from halogen, hydroxy,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R⁵ is optionallysubstituted (C₁-C₃)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, or optionally substituted 5-6 memberedmonocyclic heteroaryl; R^(a1) and R^(b1) are each independently selectedfrom —H, optionally substituted (C₁-C₆)alkyl, optionally substituted(C₃-C₇)cycloalkyl, optionally substituted 3-7 membered monocyclicheterocycloalkyl, optionally substituted phenyl, and optionallysubstituted 5-6 membered monocyclic heteroaryl; or R^(a1) and R^(b1),together with the nitrogen to which they are attached, form anoptionally substituted 3-7 membered ring; R^(a2) and R^(b2) are eachindependently selected from —H, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7membered monocyclic heterocycloalkyl, optionally substituted phenyl, andoptionally substituted 5-6 membered monocyclic heteroaryl; or R^(a2) andR^(b2), together with the nitrogen to which they are attached, form anoptionally substituted 3-8 membered ring; R^(c1) is optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₇)cycloalkyl,optionally substituted 3-7 membered monocyclic heterocycloalkyl,optionally substituted phenyl, or optionally substituted 5-6 memberedmonocyclic heteroaryl; R^(c2) is optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₇)cycloalkyl, optionally substituted 3-7membered monocyclic heterocycloalkyl, optionally substituted phenyl, oroptionally substituted 5-6 membered monocyclic heteroaryl; R^(d) andR^(e) are each independently selected from —H, optionally substituted(C₁-C₇)alkyl, optionally substituted (C₃-C₇)cycloalkyl, optionallysubstituted 3-7 membered monocyclic heterocycloalkyl, optionallysubstituted phenyl, and optionally substituted 5-6 membered monocyclicheteroaryl; or R^(d) and R^(e), together with the nitrogen to which theyare attached, form an optionally substituted 3-7 membered ring; and m is0, 1, 2, or
 3. 2. The compound of claim 1, wherein the compound isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: X is NH or O; R⁵is selected from (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl, each of which isoptionally substituted with one or more groups selected from halogen,hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; R¹¹ is(C₁-C₃)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each ofwhich is optionally substituted with one or more groups selected fromhalogen, hydroxy, CN, amino, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, —C(═O)NH₂, and —SO₂CH₃; R^(d) and R^(e) are eachindependently selected from —H, (C₁-C₇)alkyl, (C₃-C₇) cycloalkyl,wherein each of the (C₁-C₃)alkyl and (C₃-C₇)cycloalkyl is optionallysubstituted with one or more groups selected from halogen, hydroxy,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; and n is 0, 1, 2, or3.
 3. The compound of claim 2, wherein the compound is represented bythe following structural formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein R^(b2) is —H or CH₃.
 5. The compound of claim 4, whereinR^(a2) is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl;wherein each of which is optionally substituted with one or more groupsselected from halogen, hydroxy, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy.
 6. The compound of claim 5, wherein R^(a2) is methyl,ethyl, t-butyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, pyridyl,or phenyl, wherein each of the cyclopentyl, cyclohexyl,tetrahydro-2H-pyranyl, pyridyl, and phenyl is optionally substitutedwith one or more groups selected from halogen, hydroxy, CN,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 7. The compound ofclaim 3, wherein R^(a2) and R^(b2), together with the nitrogen to whichthey are attached, form a 3-7 membered monocyclic heterocycloalkyl,optionally substituted with one or more groups selected from halogen,CN, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl,(C₁-C₃)alkoxy, —C(═O)H, —C(═O)(C₃-C₇)cycloalkyl, —C(═O)(C₁-C₃)alkyl, and3-7 membered monocyclic heterocycloalkyl.
 8. The compound of claim 2,wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim8, wherein R^(c2) is (C₃-C₇)cycloalkyl, 3-7 membered monocyclicheterocycloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, each ofwhich is optionally substituted with one or more groups selected fromhalogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl,(C₁-C₃)alkoxy, —C(═O)(C₁-C₃)alkyl, —C(═O)(C₃-C₇)cycloalkyl, and —C(═O)H.10. The compound of claim 9, wherein R^(c2) is cyclopentyl, cyclohexyl,tetrahydro-2H-pyranyl, phenyl, pyridyl, or azetidinyl, wherein each ofthe cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, phenyl, and pyridylis optionally substituted with one or more groups selected from halogen,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, and (C₁-C₃)alkoxy;and the nitrogen in the azetidinyl is optionally substituted with(C₁-C₃)alkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₁-C₃)alkyl,—C(═O)(C₃—O₅)cycloalkyl, or —C(═O)H.
 11. The compound of claim 10,wherein X is NH and R⁴ is selected from hydrogen, halogen, and(C₁-C₃)alkyl.
 12. The compound of claim 2, wherein R¹¹—(CH₂)_(n)—X— isrepresented by the one of the following structural formulae:


13. The compound of claim 2, wherein R² is represented by the one of thefollowing structural formulae:


14. The compound of claim 13, wherein R⁴ is chlorine or methyl, and isortho to —C(═O)NHR^(d).
 15. The compound of claim 2, wherein R¹¹ isethyl, isopropyl, cyclohexyl, morpholinyl, tetrahydro-2H-pyranyl,piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl, whereineach substitutable carbon in the morpholinyl, tetrahydro-2H-pyranyl,piperidinyl, piperazinyl, pyridinyl, imidazolyl, or oxetanyl isoptionally substituted with —OH, halogen, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, or (C₁-C₃)alkoxy; and each substitutable nitrogen inthe piperazinyl is optionally substituted with (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₁-C₃)hydroxylalkyl, —C(═O)(C₃—O₅)cycloalkyl,—C(═O)(C₁-C₃)alkyl, or —C(═O)H.
 16. The compound of claim 15, whereinR^(d) is (C₂-C₇)alkyl or (C₃-C₇) cycloalkyl, wherein both of which areoptionally substituted with one or more groups selected from halogen,hydroxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 17. Thecompound of claim 14, wherein R^(d) is (C₂-C₇)alkyl or (C₃-C₇)cycloalkyl, wherein both of which are optionally substituted with one ormore groups selected from halogen, hydroxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy.
 18. The compound of claim 17,wherein R^(d) is cyclopropyl.
 19. A pharmaceutical compositioncomprising a compound of claim 1 and a pharmaceutically acceptablecarrier or diluent.
 20. A method for treating cancer, the methodcomprising: administering to a subject in need thereof an effectiveamount of the compound of claim
 1. 21. The method of claim 20, whereinthe cancer is pancreatic cancer, prostate cancer, lung cancer, melanoma,breast cancer, colon cancer, or ovarian cancer.